Oligonucleotide Agonists Targeting Progranulin

Description

REFERENCE TO SEQUENCE LISTING

The instant application contains a Sequence Listing which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on May 2, 2023, is named 067211.019US1.xml and is 4 MB in size.

FIELD OF INVENTION

The present invention relates to oligonucleotides which up-regulate or restore the expression of progranulin in cells, and their use in the treatment of neurological disorders, and disorders associated with progranulin haploinsufficiency.

BACKGROUND

Progranulin (PGRN) is a highly conserved secreted protein that is expressed in multiple cell types, both in the CNS and in peripheral tissues.

Deficiency of the secreted protein progranulin in the central nervous system causes the neurodegenerative disease fronto temporal dementia (FTD). Pathogenic progranulin (GRN) mutations lead to a loss of about 50% in progranulin levels through haploinsufficiency and to intraneuronal aggregation of TDP-43 protein. Progranulin plays a supportive and protective role in numerous processes within the brain, including neurite outgrowth, synapse biology, response to exogenous stressors, lysosomal function, neuroinflammation, and angiogenesis in both cell autonomous and non-autonomous manners.

In several neurodegenerative diseases TDP-43 is a common denominator. TDP-43 pathology is associated with cytoplasmic TDP-43 aggregation. For example, more than 95% of ALS patients display pathological mislocalization of TDP-43 and several mutations in its gene cause familial ALS.

The presence of cytoplasmic TDP-43 aggregates is associated with a concomitant loss of nuclear TDP-43, and there is evidence of both loss of function and gain of function associated pathophysiologies.

Both directly and via its conversion to granulins, progranulin regulates lysosomal function, cell growth, survival, repair, and inflammation. Progranulin has a major role in regulation of lysosomal function associated microglial responses in the CNS. Autosomal dominant mutations of the progranulin (GRN) gene leading to protein haploinsufficiency are linked to familial frontotemporal dementia with neuropathologic frontotemporal lobar degeneration (FTLD) associated with accumulation of TAR-DNA binding protein of 43kDA (TDP-43) inclusions (FTLD-TDP). Homozygous GRN mutations are linked to neuronal ceroid lipofuscinosis (NCL) (Townley, et al., Neurology. 2018 Jun. 12; 90(24): 1127).

Mutations in the progranulin gene (GRN) have recently been identified as a cause of about 5% of all FTD, including some sporadic cases. Recent studies using mouse models has defined the expression of PGRN in the brain (Petkau et al., 2010). PGRN is expressed late in neurodevelopment, localizing with markers of mature neurons. PGRN is expressed in neurons in most brain regions, with highest expression in the thalamus, hippocampus, and cortex. Microglia cells also express progranulin, and the level of expression is upregulated by microglial activation. Around 70 different GRN mutations have been identified in FTD and all reduce progranulin levels or result in loss of progranulin function.

WO 2020/077165 reports on AAV particle delivery of therapeutic nucleic acids, and lists progranulin as a potential gene of interest.

There is therefore an urgent need for therapeutic agents which can increase the expression of progranulin.

SUMMARY OF INVENTION

The invention provides antisense oligonucleotide agonists of progranulin or antisense oligonucleotide progranulin agonists—i.e. antisense oligonucleotides which are complementary to a progranulin nucleic acid sequence, and which are capable of up-regulating the expression of progranulin. Alternatively stated, the invention provides antisense oligonucleotide positive modulators (i.e. agonists) of progranulin.

The antisense oligonucelotides of the invention may therefore be used to restore progranulin expression in cells which exhibit progranulin haploinsufficiency, or to enhance expression of progranulin in cells.

The invention provides an antisense oligonucleotide progranulin agonist, wherein the antisense oligonucleotide is 8-40 nucleotides in length and comprises a contiguous nucleotide sequence of 8-40 nucleotides in length which are complementary, such as fully complementary, to a human progranulin precursor-mRNA (pre-mRNA) or mature mRNA transcript.

The invention provides an antisense oligonucleotide progranulin agonist, wherein the antisense oligonucleotide is 12-40 nucleotides in length and comprises a contiguous nucleotide sequence of 12-40 nucleotides in length which are complementary, such as fully complementary, to a human progranulin precursor-mRNA (pre-mRNA) or mature mRNA transcript.

The invention provides an antisense oligonucleotide progranulin agonist, wherein the antisense oligonucleotide is 12-20 nucleotides in length and comprises a contiguous nucleotide sequence of 12-20 nucleotides in length which are complementary, such as fully complementary, to a human progranulin precursor-mRNA (pre-mRNA) or mature mRNA transcript.

The invention provides an antisense oligonucleotide progranulin agonist, wherein the antisense oligonucleotide is 14-18 nucleotides in length and comprises a contiguous nucleotide sequence of 14-18 nucleotides in length which are complementary, such as fully complementary, to a human progranulin precursor-mRNA (pre-mRNA) or mature mRNA transcript.

The invention provides an antisense oligonucleotide progranulin agonist, wherein the antisense oligonucleotide is 12-18 nucleotides in length and comprises a contiguous nucleotide sequence of 12-18 nucleotides in length which are complementary, such as fully complementary, to a human progranulin precursor-mRNA (pre-mRNA) or mature mRNA transcript.

The invention provides an antisense oligonucleotide progranulin agonist, wherein the antisense oligonucleotide is 8-40 nucleotides in length and comprises a contiguous nucleotide sequence of 8-40 nucleotides in length which are complementary, such as fully complementary, to a sequence selected from the group consisting of SEQ ID NO 683, 684, 685, 686, 687 and 688.

The invention provides an antisense oligonucleotide progranulin agonist, wherein the antisense oligonucleotide is 12-40 nucleotides in length and comprises a contiguous nucleotide sequence of 12-40 nucleotides in length which are complementary, such as fully complementary, to a sequence selected from the group consisting of SEQ ID NO 683, 684, 685, 686, 687 and 688.

The invention provides an antisense oligonucleotide progranulin agonist, wherein the antisense oligonucleotide is 12-20 nucleotides in length and comprises a contiguous nucleotide sequence of 12-20 nucleotides in length which are complementary, such as fully complementary, to a sequence selected from the group consisting of SEQ ID NO 683, 684, 685, 686, 687 and 688.

The invention provides an antisense oligonucleotide progranulin agonist, wherein the antisense oligonucleotide is 14-18 nucleotides in length and comprises a contiguous nucleotide sequence of 14-18 nucleotides in length which are complementary, such as fully complementary, to a to a sequence selected from the group consisting of SEQ ID NO 683, 684, 685, 686, 687 and 688.

The invention provides an antisense oligonucleotide progranulin agonist, wherein the antisense oligonucleotide is 12-18 nucleotides in length and comprises a contiguous nucleotide sequence of 12-18 nucleotides in length which are complementary, such as fully complementary, to a sequence selected from the group consisting of SEQ ID NO 683, 684, 685, 686, 687 and 688.

The antisense oligonucleotide progranulin agonist may be 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40 nucleotides in length. In some embodiments the antisense oligonucleotide, or contiguous nucleotide sequence thereof, is 8-40, 12-40, 12-20, 14-18, 12-18 or 16-18 nucleotides in length.

The contiguous nucleotide sequence may be 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40 nucleotides in length. In some embodiments, the contiguous nucleotide sequence is of a length of at least 12 nucleotides in length, such as 12-16 or 12-18 nucleotides in length.

In some embodiments, the contiguous nucleotide sequence is the same length as the antisense oligonucleotide progranulin agonist.

In some embodiments the antisense oligonucleotide consists of the contiguous nucleotide sequence.

In some embodiments the antisense oligonucleotide is the contiguous nucleotide sequence.

In some embodiments, the contiguous nucleotide sequence is fully complementary to a sequence selected from the group consisting of SEQ ID NO 343-682.

In some embodiments the contiguous nucleotide sequence is complementary, such as fully complementary, to the human progranulin mature mRNA (SEQ ID NO: 1).

In some embodiments the contiguous nucleotide sequence is complementary, such as fully complementary, to the human progranulin precursor-mRNA (pre-mRNA) (SEQ ID NO: 3949).

In some embodiments, the contiguous nucleotide sequence is complementary, such as fully complementary, to a 5′UTR region of a human progranulin mature mRNA transcript. Herein the 5′ UTR is defined as nucleotides 38 to 241 according to RefSeq NM_002807.3 (SEQ ID NO 1).

In some embodiments, the contiguous nucleotide sequence is complementary, such as fully complementary, to nucleotides 38-246 of SEQ ID NO 1.

In some embodiments, the contiguous nucleotide sequence is complementary, such as fully complementary, to SEQ ID NO 689.

In some embodiments, the contiguous nucleotide sequence is complementary, such as fully complementary, to SEQ ID NO 2.

In some embodiments, the contiguous nucleotide sequence is complementary, such as fully complementary, to SEQ ID NO 683.

In some embodiments, the contiguous nucleotide sequence is complementary, such as fully complementary, to a sequence selected from the group consisting of SEQ ID NO 343-586.

In some embodiments, the contiguous nucleotide sequence is complementary, such as fully complementary, to a sequence selected from the group consisting of SEQ ID NO 568, SEQ ID NO 571, SEQ ID NO 575, SEQ ID NO 576, SEQ ID NO 577, SEQ ID NO 578, SEQ ID NO 584, & SEQ ID NO 586.

In some embodiments, the contiguous nucleotide sequence is a sequence selected from the group consisting of SEQ ID NO 3-342, or at least 8 contiguous nucleotides thereof.

In some embodiments, the contiguous nucleotide sequence is a sequence selected from the group consisting of SEQ ID NO 3-342, or at least 9 contiguous nucleotides thereof.

In some embodiments, the contiguous nucleotide sequence is a sequence selected from the group consisting of SEQ ID NO 3-342, or at least 10 contiguous nucleotides thereof.

In some embodiments, the contiguous nucleotide sequence is a sequence selected from the group consisting of SEQ ID NO 3-342, or at least 11 contiguous nucleotides thereof.

In some embodiments, the contiguous nucleotide sequence is a sequence selected from the group consisting of SEQ ID NO 3-342, or at least 12 contiguous nucleotides thereof.

In some embodiments, the contiguous nucleotide sequence is a sequence selected from the group consisting of SEQ ID NO 3-342, or at least 13 contiguous nucleotides thereof.

In some embodiments, the contiguous nucleotide sequence is a sequence selected from the group consisting of SEQ ID NO 3-342, or at least 14 contiguous nucleotides thereof.

In some embodiments, the contiguous nucleotide sequence is a sequence selected from the group consisting of SEQ ID NO 3-342, or at least 15 contiguous nucleotides thereof.

In some embodiments, the contiguous nucleotide sequence is a sequence selected from the group consisting of SEQ ID NO 3-342, or at least 16 contiguous nucleotides thereof.

In some embodiments, the contiguous nucleotide sequence is selected from SEQ ID NO 105, SEQ ID NO 106, SEQ ID NO 110, SEQ ID NO 113, SEQ ID NO 114, SEQ ID NO 231 and SEQ ID NO 241 or at least 8 or at least 10 contiguous nucleotides thereof.

In some embodiments the contiguous nucleotide sequence is SEQ ID NO 106.

In some embodiments the contiguous nucleotide sequence is SEQ ID NO 110.

In some embodiments, the contiguous nucleotide sequence is complementary, such as fully complementary, to a 3′UTR region of a human progranulin mature mRNA transcript. Herein the 3′ UTR is defined as nucleotides 2044 to 2346 according to RefSeq NM_002807.3 (SEQ ID NO 1).

In some embodiments, the contiguous nucleotide sequence is complementary, such as fully complementary, to nucleotides 2039-2346 of SEQ ID NO 1.

In some embodiments, the contiguous nucleotide sequence is complementary, such as fully complementary, to a sequence selected from the group consisting of SEQ ID NO 684, SEQ ID NO 685, SEQ ID NO 686, SEQ ID NO 687, and SEQ ID NO 688.

In some embodiments, the contiguous nucleotide sequence is complementary, such as fully complementary, to a sequence selected from the group consisting of SEQ ID NO 587-682.

In some embodiments, the contiguous nucleotide sequence is complementary, such as fully complementary, to a sequence selected from the group consisting of SEQ ID NO 607, SEQ ID NO 608, SEQ ID NO 609, SEQ ID NO 610, SEQ ID NO 611, SEQ ID NO 612, SEQ ID NO 619, SEQ ID NO 620, SEQ ID NO 633, SEQ ID NO 640, SEQ ID NO 641, SEQ ID NO 645, SEQ ID NO 651, and SEQ ID NO 652.

In some embodiments, the contiguous nucleotide sequence is complementary, such as fully complementary, to a sequence selected from the group consisting of SEQ ID NO 2040-3386.

In some embodiments, the contiguous nucleotide sequence is complementary, such as fully complementary, to a sequence selected from the group consisting of SEQ ID NO 2040-3386 or at least 8 contiguous nucleotides thereof.

In some embodiments, the contiguous nucleotide sequence is complementary, such as fully complementary, to a sequence selected from the group consisting of SEQ ID 2321, SEQ ID 2322, SEQ ID 2324, SEQ ID 2328, SEQ ID 2329, SEQ ID 2331, SEQ ID 2334, SEQ ID 2335, SEQ ID 2336, SEQ ID 2337, SEQ ID 2338, SEQ ID 2339, SEQ ID 2340, SEQ ID 2341, SEQ ID 2342, SEQ ID 2345, SEQ ID 2346, SEQ ID 2347, SEQ ID 2348, SEQ ID 2349, SEQ ID 2350, SEQ ID 2351, SEQ ID 2352, SEQ ID 2353, SEQ ID 2354, SEQ ID 2355, SEQ ID 2356, SEQ ID 2357, SEQ ID 2358, SEQ ID 2359, SEQ ID 2360, SEQ ID 2361, SEQ ID 2362, SEQ ID 2364, SEQ ID 2365, SEQ ID 2366, SEQ ID 2367, SEQ ID 2368, SEQ ID 2369, SEQ ID 2370, SEQ ID 2371, SEQ ID 2372, SEQ ID 2373, SEQ ID 2374, SEQ ID 2375, SEQ ID 2376, SEQ ID 2377, SEQ ID 2378, SEQ ID 2379, SEQ ID 2380, SEQ ID 2381, SEQ ID 2384, SEQ ID 2386, SEQ ID 2387, SEQ ID 2388, SEQ ID 2389, SEQ ID 2390, SEQ ID 2392, SEQ ID 2393, SEQ ID 2394, SEQ ID 2395, SEQ ID 2396, SEQ ID 2397, SEQ ID 2398, SEQ ID 2399, SEQ ID 2400, SEQ ID 2401, SEQ ID 2403, SEQ ID 2404, SEQ ID 2405, SEQ ID 2406, SEQ ID 2407, SEQ ID 2408, SEQ ID 2410, SEQ ID 2411, SEQ ID 2413, SEQ ID 2414, SEQ ID 2415, SEQ ID 2416, SEQ ID 2418, SEQ ID 2419, SEQ ID 2421, SEQ ID 2424, SEQ ID 2425, SEQ ID 2426, SEQ ID 2427, SEQ ID 2428, SEQ ID 2429, SEQ ID 2430, SEQ ID 2431, SEQ ID 2432, SEQ ID 2433, SEQ ID 2434, SEQ ID 2435, SEQ ID 2436, SEQ ID 2437, SEQ ID 2438, SEQ ID 2439, SEQ ID 2440, SEQ ID 2441, SEQ ID 2442, SEQ ID 2443, SEQ ID 2444, SEQ ID 2445, SEQ ID 2446, SEQ ID 2447, SEQ ID 2448, SEQ ID 2449, SEQ ID 2450, SEQ ID 2451, SEQ ID 2452, SEQ ID 2453, SEQ ID 2454, SEQ ID 2455, SEQ ID 2456, SEQ ID 2457, SEQ ID 2458, SEQ ID 2459, SEQ ID 2460, SEQ ID 2461, SEQ ID 2462, SEQ ID 2463, SEQ ID 2464, SEQ ID 2465, SEQ ID 2466, SEQ ID 2467, SEQ ID 2468, SEQ ID 2469, SEQ ID 2470, SEQ ID 2471, SEQ ID 2472, SEQ ID 2473, SEQ ID 2474, SEQ ID 2475, SEQ ID 2476, SEQ ID 2477, SEQ ID 2478, SEQ ID 2479, SEQ ID 2481, SEQ ID 2482, SEQ ID 2483, SEQ ID 2484, SEQ ID 2485, SEQ ID 2487, SEQ ID 2489, SEQ ID 2490, SEQ ID 2491, SEQ ID 2492, SEQ ID 2493, SEQ ID 2494, SEQ ID 2495, SEQ ID 2496, SEQ ID 2497, SEQ ID 2498, SEQ ID 2499, SEQ ID 2501, SEQ ID 2502, SEQ ID 2503, SEQ ID 2504, SEQ ID 2505, SEQ ID 2506, SEQ ID 2507, SEQ ID 2508, SEQ ID 2509, SEQ ID 2510, SEQ ID 2511, SEQ ID 2512, SEQ ID 2513, SEQ ID 2514, SEQ ID 2515, SEQ ID 2516, SEQ ID 2518, SEQ ID 2519, SEQ ID 2520, SEQ ID 2521, SEQ ID 2522, SEQ ID 2523, SEQ ID 2524, SEQ ID 2525, SEQ ID 2526, SEQ ID 2527, SEQ ID 2528, SEQ ID 2531, SEQ ID 2533, SEQ ID 2534, SEQ ID 2535, SEQ ID 2536, SEQ ID 2537, SEQ ID 2538, SEQ ID 2540, SEQ ID 2541, SEQ ID 2542, SEQ ID 2544, SEQ ID 2546, SEQ ID 2547, SEQ ID 2549, SEQ ID 2550, SEQ ID 2551, SEQ ID 2553, SEQ ID 2554, SEQ ID 2555, SEQ ID 2556, SEQ ID 2557, SEQ ID 2560, SEQ ID 2561, SEQ ID 2562, SEQ ID 2563, SEQ ID 2565, SEQ ID 2566, SEQ ID 2567, SEQ ID 2572, SEQ ID 2573, SEQ ID 2574, SEQ ID 2575, SEQ ID 2576, SEQ ID 2577, SEQ ID 2578, SEQ ID 2579, SEQ ID 2580, SEQ ID 2581, SEQ ID 2582, SEQ ID 2583, SEQ ID 2584, SEQ ID 2585, SEQ ID 2586, SEQ ID 2588, SEQ ID 2589, SEQ ID 2590, SEQ ID 2591, SEQ ID 2592, SEQ ID 2593, SEQ ID 2594, SEQ ID 2595, SEQ ID 2596, SEQ ID 2597, SEQ ID 2598, SEQ ID 2599, SEQ ID 2601, SEQ ID 2602, SEQ ID 2603, SEQ ID 2604, SEQ ID 2606, SEQ ID 2610, SEQ ID 2613, SEQ ID 2614, SEQ ID 2615, SEQ ID 2619, SEQ ID 2622, SEQ ID 2623, SEQ ID 2624, SEQ ID 2625, SEQ ID 2626, SEQ ID 2627, SEQ ID 2628, SEQ ID 2629, SEQ ID 2630, SEQ ID 2631, SEQ ID 2632, SEQ ID 2633, SEQ ID 2634, SEQ ID 2635, SEQ ID 2636, SEQ ID 2637, SEQ ID 2638, SEQ ID 2639, SEQ ID 2640, SEQ ID 2641, SEQ ID 2642, SEQ ID 2643, SEQ ID 2644, SEQ ID 2645, SEQ ID 2646, SEQ ID 2647, SEQ ID 2648, SEQ ID 2649, SEQ ID 2650, SEQ ID 2651, SEQ ID 2652, SEQ ID 2653, SEQ ID 2654, SEQ ID 2655, SEQ ID 2656, SEQ ID 2658, SEQ ID 2659, SEQ ID 2660, SEQ ID 2661, SEQ ID 2662, SEQ ID 2663, SEQ ID 2664, SEQ ID 2665, SEQ ID 2666, SEQ ID 2667, SEQ ID 2668, SEQ ID 2669, SEQ ID 2670, SEQ ID 2671, SEQ ID 2672, SEQ ID 2673, SEQ ID 2674, SEQ ID 2675, SEQ ID 2676, SEQ ID 2677, SEQ ID 2678, SEQ ID 2679, SEQ ID 2680, SEQ ID 2681, SEQ ID 2682, SEQ ID 2683, SEQ ID 2684, SEQ ID 2685, SEQ ID 2686, SEQ ID 2687, SEQ ID 2688, SEQ ID 2689, SEQ ID 2690, SEQ ID 2691, SEQ ID 2693, SEQ ID 2694, SEQ ID 2695, SEQ ID 2696, SEQ ID 2697, SEQ ID 2698, SEQ ID 2699, SEQ ID 2700, SEQ ID 2701, SEQ ID 2702, SEQ ID 2703, SEQ ID 2704, SEQ ID 2705, SEQ ID 2706, SEQ ID 2707, SEQ ID 2708, SEQ ID 2709, SEQ ID 2710, SEQ ID 2711, SEQ ID 2712, SEQ ID 2713, SEQ ID 2714, SEQ ID 2715, SEQ ID 2716, SEQ ID 2717, SEQ ID 2718, SEQ ID 2719, SEQ ID 2720, SEQ ID 2721, SEQ ID 2722, SEQ ID 2723, SEQ ID 2726, SEQ ID 2727, SEQ ID 2728, SEQ ID 2729, SEQ ID 2730, SEQ ID 2733, SEQ ID 2734, SEQ ID 2735, SEQ ID 2736, SEQ ID 2737, SEQ ID 2738, SEQ ID 2739, SEQ ID 2740, SEQ ID 2741, SEQ ID 2742, SEQ ID 2743, SEQ ID 2744, SEQ ID 2745, SEQ ID 2746, SEQ ID 2747, SEQ ID 2748, SEQ ID 2749, SEQ ID 2750, SEQ ID 2751, SEQ ID 2752, SEQ ID 2753, SEQ ID 2754, SEQ ID 2755, SEQ ID 2756, SEQ ID 2757, SEQ ID 2758, SEQ ID 2759, SEQ ID 2760, SEQ ID 2761, SEQ ID 2762, SEQ ID 2763, SEQ ID 2764, SEQ ID 2765, SEQ ID 2766, SEQ ID 2767, SEQ ID 2768, SEQ ID 2769, SEQ ID 2770, SEQ ID 2771, SEQ ID 2772, SEQ ID 2773, SEQ ID 2774, SEQ ID 2775, SEQ ID 2815, SEQ ID 2816, SEQ ID 2817, SEQ ID 2818, SEQ ID 2819, SEQ ID 2820, SEQ ID 2821, SEQ ID 2822, SEQ ID 2823, SEQ ID 2824, SEQ ID 2825, SEQ ID 2826, SEQ ID 2827, SEQ ID 2828, SEQ ID 2829, SEQ ID 2830, SEQ ID 2831, SEQ ID 2832, SEQ ID 2833, SEQ ID 2834, SEQ ID 2835, SEQ ID 2836, SEQ ID 2837, SEQ ID 2838, SEQ ID 2839, SEQ ID 2840, SEQ ID 2841, SEQ ID 2842, SEQ ID 2843, SEQ ID 2844, SEQ ID 2845, SEQ ID 2847, SEQ ID 2848, SEQ ID 2849, SEQ ID 2850, SEQ ID 2851, SEQ ID 2852, SEQ ID 2853, SEQ ID 2854, SEQ ID 2855, SEQ ID 2858, SEQ ID 2859, SEQ ID 2860, SEQ ID 2861, SEQ ID 2862, SEQ ID 2863, SEQ ID 2864, SEQ ID 2865, SEQ ID 2866, SEQ ID 2867, SEQ ID 2868, SEQ ID 2869, SEQ ID 2870, SEQ ID 2871, SEQ ID 2872, SEQ ID 2873, SEQ ID 2874, SEQ ID 2875, SEQ ID 2876, SEQ ID 2878, SEQ ID 2879, SEQ ID 2880, SEQ ID 2881, SEQ ID 2882, SEQ ID 2883, SEQ ID 2884, SEQ ID 2885, SEQ ID 2886, SEQ ID 2887, SEQ ID 2888, SEQ ID 2889, SEQ ID 2890, SEQ ID 2891, SEQ ID 2892, SEQ ID 2893, SEQ ID 2894, SEQ ID 2895, SEQ ID 2896, SEQ ID 2897, SEQ ID 2898, SEQ ID 2899, SEQ ID 2900, SEQ ID 2901, SEQ ID 2902, SEQ ID 2903, SEQ ID 2904, SEQ ID 2905, SEQ ID 2906, SEQ ID 2907, SEQ ID 2908, SEQ ID 2909, SEQ ID 2910, SEQ ID 2911, SEQ ID 2912, SEQ ID 2913, SEQ ID 2914, SEQ ID 2915, SEQ ID 2916, SEQ ID 2917, SEQ ID 2918, SEQ ID 2919, SEQ ID 2920, SEQ ID 2921, SEQ ID 2922, SEQ ID 2923, SEQ ID 2924, SEQ ID 2925, SEQ ID 2926, SEQ ID 2927, SEQ ID 2928, SEQ ID 2929, SEQ ID 2930, SEQ ID 2931, SEQ ID 2932, SEQ ID 2934, SEQ ID 2935, SEQ ID 2936, SEQ ID 2937, SEQ ID 2938, SEQ ID 2939, SEQ ID 2940, SEQ ID 2941, SEQ ID 2942, SEQ ID 2943, SEQ ID 2944, SEQ ID 2945, SEQ ID 2946, SEQ ID 2947, SEQ ID 2948, SEQ ID 2949, SEQ ID 2950, SEQ ID 2951, SEQ ID 2953, SEQ ID 2954, SEQ ID 2955, SEQ ID 2956, SEQ ID 2957, SEQ ID 2958, SEQ ID 2960, SEQ ID 2961, SEQ ID 2963, SEQ ID 2964, SEQ ID 2965, SEQ ID 2966, SEQ ID 2967, SEQ ID 2969, SEQ ID 2970, SEQ ID 2971, SEQ ID 2972, SEQ ID 2973, SEQ ID 2974, SEQ ID 2975, SEQ ID 2976, SEQ ID 2977, SEQ ID 2978, SEQ ID 2979, SEQ ID 2980, SEQ ID 2981, SEQ ID 2982, SEQ ID 2983, SEQ ID 2984, SEQ ID 2985, SEQ ID 3053, SEQ ID 3054, SEQ ID 3055, SEQ ID 3056, SEQ ID 3057, SEQ ID 3058, SEQ ID 3059, SEQ ID 3060, SEQ ID 3061, SEQ ID 3062, SEQ ID 3063, SEQ ID 3064, SEQ ID 3065, SEQ ID 3066, SEQ ID 3068, SEQ ID 3069, SEQ ID 3070, SEQ ID 3071, SEQ ID 3072, SEQ ID 3073, SEQ ID 3074, SEQ ID 3075, SEQ ID 3076, SEQ ID 3077, SEQ ID 3078, SEQ ID 3079, SEQ ID 3080, SEQ ID 3081, SEQ ID 3082, SEQ ID 3083, SEQ ID 3084, SEQ ID 3085, SEQ ID 3086, SEQ ID 3087, SEQ ID 3088, SEQ ID 3089, SEQ ID 3090, SEQ ID 3091, SEQ ID 3092, SEQ ID 3093, SEQ ID 3094, SEQ ID 3095, SEQ ID 3097, SEQ ID 3098, SEQ ID 3099, SEQ ID 3100, SEQ ID 3102, SEQ ID 3103, SEQ ID 3104, SEQ ID 3105, SEQ ID 3106, SEQ ID 3107, SEQ ID 3108, SEQ ID 3109, SEQ ID 3110, SEQ ID 3112, SEQ ID 3113, SEQ ID 3115, SEQ ID 3116, SEQ ID 3117, SEQ ID 3119, SEQ ID 3120, SEQ ID 3121, SEQ ID 3122, SEQ ID 3123, SEQ ID 3124, SEQ ID 3125, SEQ ID 3126, SEQ ID 3127, SEQ ID 3128, SEQ ID 3129, SEQ ID 3130, SEQ ID 3131, SEQ ID 3132, SEQ ID 3133, SEQ ID 3134, SEQ ID 3135, SEQ ID 3136, SEQ ID 3137, SEQ ID 3138, SEQ ID 3139, SEQ ID 3140, SEQ ID 3141, SEQ ID 3142, SEQ ID 3143, SEQ ID 3144, SEQ ID 3145, SEQ ID 3146, SEQ ID 3147, SEQ ID 3148, SEQ ID 3149, SEQ ID 3150, SEQ ID 3151, SEQ ID 3152, SEQ ID 3153, SEQ ID 3154, SEQ ID 3155, SEQ ID 3156, SEQ ID 3157, SEQ ID 3158, SEQ ID 3159, SEQ ID 3160, SEQ ID 3161, SEQ ID 3162, SEQ ID 3163, SEQ ID 3164, SEQ ID 3165, SEQ ID 3166, SEQ ID 3167, SEQ ID 3168, SEQ ID 3169, SEQ ID 3170, SEQ ID 3171, SEQ ID 3172, SEQ ID 3173, SEQ ID 3174, SEQ ID 3175, SEQ ID 3176, SEQ ID 3177, SEQ ID 3178, SEQ ID 3179, SEQ ID 3180, SEQ ID 3181, SEQ ID 3182, SEQ ID 3183, SEQ ID 3184, SEQ ID 3185, SEQ ID 3186, SEQ ID 3187, SEQ ID 3188, SEQ ID 3189, SEQ ID 3190, SEQ ID 3191, SEQ ID 3192, SEQ ID 3193, SEQ ID 3194, SEQ ID 3195, SEQ ID 3196, SEQ ID 3197, SEQ ID 3198, SEQ ID 3199, SEQ ID 3200, SEQ ID 3201, SEQ ID 3202, SEQ ID 3203, SEQ ID 3204, SEQ ID 3205, SEQ ID 3206, SEQ ID 3207, SEQ ID 3208, SEQ ID 3209, SEQ ID 3210, SEQ ID 3211, SEQ ID 3212, SEQ ID 3213, SEQ ID 3214, SEQ ID 3215, SEQ ID 3216, SEQ ID 3217, SEQ ID 3218, SEQ ID 3219, SEQ ID 3220, SEQ ID 3221, SEQ ID 3222, SEQ ID 3223, SEQ ID 3224, SEQ ID 3225, SEQ ID 3226, SEQ ID 3227, SEQ ID 3228, SEQ ID 3229, SEQ ID 3230, SEQ ID 3231, SEQ ID 3232, SEQ ID 3233, SEQ ID 3234, SEQ ID 3235, SEQ ID 3236, SEQ ID 3237, SEQ ID 3238, SEQ ID 3239, SEQ ID 3240, SEQ ID 3241, SEQ ID 3242, SEQ ID 3243, SEQ ID 3244, SEQ ID 3245, SEQ ID 3246, SEQ ID 3248, SEQ ID 3249, SEQ ID 3250, SEQ ID 3251, SEQ ID 3252, SEQ ID 3253, SEQ ID 3254, SEQ ID 3255, SEQ ID 3256, SEQ ID 3257, SEQ ID 3258, SEQ ID 3259, SEQ ID 3260, SEQ ID 3261, SEQ ID 3262, SEQ ID 3263, SEQ ID 3264, SEQ ID 3265, SEQ ID 3266, SEQ ID 3267, SEQ ID 3268, SEQ ID 3269, SEQ ID 3270, SEQ ID 3271, SEQ ID 3272, SEQ ID 3273, SEQ ID 3275, SEQ ID 3276, SEQ ID 3277, SEQ ID 3278, SEQ ID 3279, SEQ ID 3280, SEQ ID 3282, SEQ ID 3284, SEQ ID 3285, SEQ ID 3286, SEQ ID 3287, SEQ ID 3288, SEQ ID 3289, SEQ ID 3291, SEQ ID 3292, SEQ ID 3293, SEQ ID 3294, SEQ ID 3295, SEQ ID 3296, SEQ ID 3297, SEQ ID 3298, SEQ ID 3299, SEQ ID 3300, SEQ ID 3301, SEQ ID 3302, SEQ ID 3303, SEQ ID 3304, SEQ ID 3305, SEQ ID 3306, SEQ ID 3307, SEQ ID 3308, SEQ ID 3309, SEQ ID 3310, SEQ ID 3311, SEQ ID 3312, SEQ ID 3313, SEQ ID 3314, SEQ ID 3315, SEQ ID 3316, SEQ ID 3317, SEQ ID 3318, SEQ ID 3320, SEQ ID 3321, SEQ ID 3322, SEQ ID 3323, SEQ ID 3324, SEQ ID 3325, SEQ ID 3326, SEQ ID 3327, SEQ ID 3329, SEQ ID 3331, SEQ ID 3332, SEQ ID 3333, SEQ ID 3334, SEQ ID 3335, SEQ ID 3336, SEQ ID 3337, SEQ ID 3338, SEQ ID 3339, SEQ ID 3340, SEQ ID 3342, SEQ ID 3343, SEQ ID 3344, SEQ ID 3345, SEQ ID 3346, SEQ ID 3347, SEQ ID 3348, SEQ ID 3349, SEQ ID 3350, SEQ ID 3351, SEQ ID 3352, SEQ ID 3353, SEQ ID 3354, SEQ ID 3355, SEQ ID 3356, SEQ ID 3357, SEQ ID 3358, SEQ ID 3359, SEQ ID 3360, SEQ ID 3361, SEQ ID 3362, SEQ ID 3363, SEQ ID 3364, SEQ ID 3365, SEQ ID 3366, SEQ ID 3367, SEQ ID 3368, SEQ ID 3369, SEQ ID 3370, SEQ ID 3371, SEQ ID 3390, SEQ ID 3391, SEQ ID 3392, SEQ ID 3393, SEQ ID 3394, SEQ ID 3395, SEQ ID 3396, SEQ ID 3397, SEQ ID 3398, SEQ ID 3399, SEQ ID 3400, SEQ ID 3401, SEQ ID 3402, SEQ ID 3403, SEQ ID 3404, SEQ ID 3405, SEQ ID 3406, SEQ ID 3407, SEQ ID 3408, SEQ ID 3409, SEQ ID 3410, SEQ ID 3411, SEQ ID 3412, SEQ ID 3413, SEQ ID 3414, SEQ ID 3415, SEQ ID 3416, SEQ ID 3417, SEQ ID 3418, SEQ ID 3419, SEQ ID 3420, SEQ ID 3421, SEQ ID 3422, SEQ ID 3423, SEQ ID 3424, SEQ ID 3425, SEQ ID 3426, SEQ ID 3427, SEQ ID 3428, SEQ ID 3429, SEQ ID 3430, SEQ ID 3431, SEQ ID 3432, SEQ ID 3433, SEQ ID 3434, SEQ ID 3435, SEQ ID 3436, SEQ ID 3437, SEQ ID 3438, SEQ ID 3439, SEQ ID 3440, SEQ ID 3441, SEQ ID 3442, SEQ ID 3443, SEQ ID 3444, SEQ ID 3445, SEQ ID 3446, SEQ ID 3447, SEQ ID 3448, SEQ ID 3449, SEQ ID 3450, SEQ ID 3451, SEQ ID 3452, SEQ ID 3453, SEQ ID 3454, SEQ ID 3460, SEQ ID 3461, SEQ ID 3464, SEQ ID 3465, SEQ ID 3466, SEQ ID 3467, SEQ ID 3468, SEQ ID 3486, SEQ ID 3487, SEQ ID 3488, SEQ ID 3489, SEQ ID 3490, SEQ ID 3491, SEQ ID 3493, SEQ ID 3494, SEQ ID 3496, SEQ ID 3497, SEQ ID 3501, SEQ ID 3505, SEQ ID 3508, SEQ ID 3511, SEQ ID 3512, SEQ ID 3516, SEQ ID 3517, SEQ ID 3518, SEQ ID 3521, SEQ ID 3522, SEQ ID 3523, SEQ ID 3524, SEQ ID 3525, SEQ ID 3526, SEQ ID 3527, SEQ ID 3528, SEQ ID 3530, SEQ ID 3531, SEQ ID 3532, SEQ ID 3534, SEQ ID 3535, SEQ ID 3536, SEQ ID 3538, SEQ ID 3539, SEQ ID 3541, SEQ ID 3542, SEQ ID 3543, SEQ ID 3544, SEQ ID 3546, SEQ ID 3548, SEQ ID 3549, SEQ ID 3550, SEQ ID 3552, SEQ ID 3556, SEQ ID 3557, SEQ ID 3558, SEQ ID 3560, SEQ ID 3561, SEQ ID 3566, SEQ ID 3567, SEQ ID 3568, SEQ ID 3569, SEQ ID 3571, SEQ ID 3572, SEQ ID 3573, SEQ ID 3574, SEQ ID 3576, SEQ ID 3577, SEQ ID 3578, SEQ ID 3580, SEQ ID 3581, SEQ ID 3584, SEQ ID 3585, SEQ ID 3586, SEQ ID 3588, SEQ ID 3590, SEQ ID 3592, SEQ ID 3594, SEQ ID 3595, SEQ ID 3598, SEQ ID 3599, SEQ ID 3600, SEQ ID 3601, SEQ ID 3602, SEQ ID 3603, SEQ ID 3605, SEQ ID 3607, SEQ ID 3609, SEQ ID 3610, SEQ ID 3613, SEQ ID 3614, SEQ ID 3615, SEQ ID 3616, SEQ ID 3617, SEQ ID 3621, SEQ ID 3623, SEQ ID 3624, SEQ ID 3625, SEQ ID 3626, SEQ ID 3627, SEQ ID 3628, SEQ ID 3629, SEQ ID 3630, SEQ ID 3631, SEQ ID 3632, SEQ ID 3633, SEQ ID 3636, SEQ ID 3637, SEQ ID 3638, SEQ ID 3639, SEQ ID 3641, SEQ ID 3642, SEQ ID 3643, SEQ ID 3645, SEQ ID 3647, SEQ ID 3648, SEQ ID 3649, SEQ ID 3651, SEQ ID 3654, SEQ ID 3656, SEQ ID 3659, SEQ ID 3660, SEQ ID 3661, SEQ ID 3663, SEQ ID 3664, SEQ ID 3665, SEQ ID 3666, SEQ ID 3670, SEQ ID 3672, SEQ ID 3676, SEQ ID 3678, SEQ ID 3679, SEQ ID 3680, SEQ ID 3681, SEQ ID 3682, SEQ ID 3683, SEQ ID 3684, SEQ ID 3685, SEQ ID 3686, SEQ ID 3687, SEQ ID 3688, SEQ ID 3689, SEQ ID 3690, SEQ ID 3691, SEQ ID 3692, SEQ ID 3693, SEQ ID 3694, SEQ ID 3695, SEQ ID 3696, SEQ ID 3697, SEQ ID 3698, SEQ ID 3699, SEQ ID 3700, SEQ ID 3701, SEQ ID 3702, SEQ ID 3703, SEQ ID 3704, SEQ ID 3705, SEQ ID 3706, SEQ ID 3707, SEQ ID 3708, SEQ ID 3709, SEQ ID 3710, SEQ ID 3711, SEQ ID 3712, SEQ ID 3713, SEQ ID 3714, SEQ ID 3715, SEQ ID 3716, SEQ ID 3717, SEQ ID 3718, SEQ ID 3719, SEQ ID 3720, SEQ ID 3721, SEQ ID 3722, SEQ ID 3723, SEQ ID 3724, SEQ ID 3725, SEQ ID 3726, SEQ ID 3727, SEQ ID 3729, SEQ ID 3730, SEQ ID 3731, SEQ ID 3732, SEQ ID 3733, SEQ ID 3734, SEQ ID 3735, SEQ ID 3736, SEQ ID 3737, SEQ ID 3738, SEQ ID 3739, SEQ ID 3740, SEQ ID 3741, SEQ ID 3742, SEQ ID 3743, SEQ ID 3744, SEQ ID 3745, SEQ ID 3746, SEQ ID 3747, SEQ ID 3748, SEQ ID 3749, SEQ ID 3750, SEQ ID 3751, SEQ ID 3752, SEQ ID 3753, SEQ ID 3754, SEQ ID 3755, SEQ ID 3774, SEQ ID 3775, SEQ ID 3776, SEQ ID 3777, SEQ ID 3778, SEQ ID 3779, SEQ ID 3780, SEQ ID 3781, SEQ ID 3782, SEQ ID 3783, SEQ ID 3784, SEQ ID 3785, SEQ ID 3786, SEQ ID 3787, SEQ ID 3788, SEQ ID 3789, SEQ ID 3790, SEQ ID 3791, SEQ ID 3792, SEQ ID 3793, SEQ ID 3794, SEQ ID 3795, SEQ ID 3796, SEQ ID 3797, SEQ ID 3798, SEQ ID 3799, SEQ ID 3800, SEQ ID 3801, SEQ ID 3802, SEQ ID 3803, SEQ ID 3804, SEQ ID 3805, SEQ ID 3806, SEQ ID 3807, SEQ ID 3808, SEQ ID 3809, SEQ ID 3810, SEQ ID 3811, SEQ ID 3812, SEQ ID 3813, SEQ ID 3814, SEQ ID 3815, SEQ ID 3816, SEQ ID 3817, SEQ ID 3818, SEQ ID 3819, SEQ ID 3820, SEQ ID 3821, SEQ ID 3822, SEQ ID 3823, SEQ ID 3824, SEQ ID 3825, SEQ ID 3826, SEQ ID 3827, SEQ ID 3828, SEQ ID 3829, SEQ ID 3830, SEQ ID 3831, SEQ ID 3832, SEQ ID 3833, SEQ ID 3834, SEQ ID 3835, SEQ ID 3836, SEQ ID 3837, SEQ ID 3838, SEQ ID 3839, SEQ ID 3840, SEQ ID 3841, SEQ ID 3842, SEQ ID 3844, SEQ ID 3848, SEQ ID 3850, SEQ ID 3851, SEQ ID 3852, SEQ ID 3853, SEQ ID 3867, SEQ ID 3868, SEQ ID 3869, SEQ ID 3870, SEQ ID 3871, SEQ ID 3872, SEQ ID 3873, SEQ ID 3874, SEQ ID 3875, SEQ ID 3876, SEQ ID 3877, SEQ ID 3878, SEQ ID 3879, SEQ ID 3880, SEQ ID 3881, SEQ ID 3882, SEQ ID 3883, SEQ ID 3884, SEQ ID 3885, SEQ ID 3886, SEQ ID 3887, SEQ ID 3888, SEQ ID 3889, SEQ ID 3890, SEQ ID 3891, SEQ ID 3892, SEQ ID 3893, SEQ ID 3894, SEQ ID 3895, SEQ ID 3896, SEQ ID 3897, SEQ ID 3898, SEQ ID 3899, SEQ ID 3900, SEQ ID 3901, SEQ ID 3902, SEQ ID 3903, SEQ ID 3904, SEQ ID 3905, SEQ ID 3906, SEQ ID 3907, SEQ ID 3908, SEQ ID 3909, SEQ ID 3910, SEQ ID 3911, SEQ ID 3912, SEQ ID 3913, SEQ ID 3914, SEQ ID 3915, SEQ ID 3916, SEQ ID 3917, SEQ ID 3918, SEQ ID 3919, SEQ ID 3920, SEQ ID 3921, SEQ ID 3922, SEQ ID 3923, SEQ ID 3924, SEQ ID 3925, SEQ ID 3926, SEQ ID 3927, SEQ ID 3928, SEQ ID 3929, SEQ ID 3930, SEQ ID 3931, SEQ ID 3932, SEQ ID 3933, SEQ ID 3934, SEQ ID 3935, SEQ ID 3936, SEQ ID 3937, SEQ ID 3938, SEQ ID 3939, SEQ ID 3940, SEQ ID 3941, SEQ ID 3942, SEQ ID 3943, SEQ ID 3944, SEQ ID 3945, SEQ ID 3946, SEQ ID 3947, and SEQ ID 3948, or at least 8, 9, 10, 11, 12, 13, 14, 15 or 16 contiguous nucleotides thereof.

In some embodiments the contiguous nucleotide sequence is complementary, such as fully complementary, to at least 8 contiguous nucleotides of any of the target sequences recited herein.

In some embodiments the contiguous nucleotide sequence is complementary, such as fully complementary, to at least 9 contiguous nucleotides of any of the target sequences recited herein.

In some embodiments the contiguous nucleotide sequence is complementary, such as fully complementary, to at least 10 contiguous nucleotides contiguous nucleotides of any of the target sequences recited herein.

In some embodiments the contiguous nucleotide sequence is complementary, such as fully complementary, to at least 11 contiguous nucleotides contiguous nucleotides of any of the target sequences recited herein.

In some embodiments the contiguous nucleotide sequence is complementary, such as fully complementary, to at least 12 contiguous nucleotides contiguous nucleotides of any of the target sequences recited herein.

In some embodiments the contiguous nucleotide sequence is complementary, such as fully complementary, to at least 13 contiguous nucleotides contiguous nucleotides of any of the target sequences recited herein.

In some embodiments the contiguous nucleotide sequence is complementary, such as fully complementary, to at least 14 contiguous nucleotides contiguous nucleotides of any of the target sequences recited herein.

In some embodiments the contiguous nucleotide sequence is complementary, such as fully complementary, to at least 15 contiguous nucleotides contiguous nucleotides of any of the target sequences recited herein.

In some embodiments the contiguous nucleotide sequence is complementary, such as fully complementary, to at least 16 contiguous nucleotides contiguous nucleotides of any of the target sequences recited herein.

In some embodiments, the antisense oligonucleotide progranulin agonist is or comprises an antisense oligonucleotide mixmer or totalmer. In some embodiments, the contiguous nucleotide sequence is a mixmer or a tolalmer.

In some embodiments, the antisense oligonucleotide progranulin agonist or contiguous nucleotide sequence thereof is 10-20 nucleotides in length.

In some embodiments, the antisense oligonucleotide progranulin agonist is selected from the group consisting of SEQ ID NOs 3-342.

In some embodiments, the antisense oligonucleotide progranulin agonist is selected from the group consisting of SEQ ID NOs 693-2039.

In some embodiments, the antisense oligonucleotide progranulin agonist is selected from the group consisting of SEQ ID 693, SEQ ID 694, SEQ ID 696, SEQ ID 700, SEQ ID 701, SEQ ID 703, SEQ ID 706, SEQ ID 707, SEQ ID 708, SEQ ID 709, SEQ ID 710, SEQ ID 711, SEQ ID 712, SEQ ID 713, SEQ ID 714, SEQ ID 717, SEQ ID 718, SEQ ID 719, SEQ ID 720, SEQ ID 721, SEQ ID 722, SEQ ID 723, SEQ ID 724, SEQ ID 725, SEQ ID 726, SEQ ID 727, SEQ ID 728, SEQ ID 729, SEQ ID 730, SEQ ID 731, SEQ ID 732, SEQ ID 733, SEQ ID 734, SEQ ID 736, SEQ ID 737, SEQ ID 738, SEQ ID 739, SEQ ID 740, SEQ ID 741, SEQ ID 742, SEQ ID 743, SEQ ID 744, SEQ ID 745, SEQ ID 746, SEQ ID 747, SEQ ID 748, SEQ ID 749, SEQ ID 750, SEQ ID 751, SEQ ID 752, SEQ ID 753, SEQ ID 756, SEQ ID 758, SEQ ID 759, SEQ ID 760, SEQ ID 761, SEQ ID 762, SEQ ID 764, SEQ ID 765, SEQ ID 766, SEQ ID 767, SEQ ID 768, SEQ ID 769, SEQ ID 770, SEQ ID 771, SEQ ID 772, SEQ ID 773, SEQ ID 775, SEQ ID 776, SEQ ID 777, SEQ ID 778, SEQ ID 779, SEQ ID 780, SEQ ID 782, SEQ ID 783, SEQ ID 785, SEQ ID 786, SEQ ID 787, SEQ ID 788, SEQ ID 790, SEQ ID 791, SEQ ID 793, SEQ ID 796, SEQ ID 797, SEQ ID 798, SEQ ID 799, SEQ ID 800, SEQ ID 801, SEQ ID 802, SEQ ID 803, SEQ ID 804, SEQ ID 805, SEQ ID 806, SEQ ID 807, SEQ ID 808, SEQ ID 809, SEQ ID 810, SEQ ID 811, SEQ ID 812, SEQ ID 813, SEQ ID 814, SEQ ID 815, SEQ ID 816, SEQ ID 817, SEQ ID 818, SEQ ID 819, SEQ ID 820, SEQ ID 821, SEQ ID 822, SEQ ID 823, SEQ ID 824, SEQ ID 825, SEQ ID 826, SEQ ID 827, SEQ ID 828, SEQ ID 829, SEQ ID 830, SEQ ID 831, SEQ ID 832, SEQ ID 833, SEQ ID 834, SEQ ID 835, SEQ ID 836, SEQ ID 837, SEQ ID 838, SEQ ID 839, SEQ ID 840, SEQ ID 841, SEQ ID 842, SEQ ID 843, SEQ ID 844, SEQ ID 845, SEQ ID 846, SEQ ID 847, SEQ ID 848, SEQ ID 849, SEQ ID 850, SEQ ID 851, SEQ ID 853, SEQ ID 854, SEQ ID 855, SEQ ID 856, SEQ ID 857, SEQ ID 859, SEQ ID 861, SEQ ID 862, SEQ ID 863, SEQ ID 864, SEQ ID 865, SEQ ID 866, SEQ ID 867, SEQ ID 868, SEQ ID 869, SEQ ID 870, SEQ ID 871, SEQ ID 873, SEQ ID 874, SEQ ID 875, SEQ ID 876, SEQ ID 877, SEQ ID 878, SEQ ID 879, SEQ ID 880, SEQ ID 881, SEQ ID 882, SEQ ID 883, SEQ ID 884, SEQ ID 885, SEQ ID 886, SEQ ID 887, SEQ ID 888, SEQ ID 890, SEQ ID 891, SEQ ID 892, SEQ ID 893, SEQ ID 894, SEQ ID 895, SEQ ID 896, SEQ ID 897, SEQ ID 898, SEQ ID 899, SEQ ID 900, SEQ ID 903, SEQ ID 905, SEQ ID 906, SEQ ID 907, SEQ ID 908, SEQ ID 909, SEQ ID 910, SEQ ID 912, SEQ ID 913, SEQ ID 914, SEQ ID 916, SEQ ID 918, SEQ ID 919, SEQ ID 921, SEQ ID 922, SEQ ID 923, SEQ ID 925, SEQ ID 926, SEQ ID 927, SEQ ID 928, SEQ ID 929, SEQ ID 932, SEQ ID 933, SEQ ID 934, SEQ ID 935, SEQ ID 937, SEQ ID 938, SEQ ID 939, SEQ ID 944, SEQ ID 945, SEQ ID 946, SEQ ID 947, SEQ ID 948, SEQ ID 949, SEQ ID 950, SEQ ID 951, SEQ ID 952, SEQ ID 953, SEQ ID 954, SEQ ID 955, SEQ ID 956, SEQ ID 957, SEQ ID 958, SEQ ID 960, SEQ ID 961, SEQ ID 962, SEQ ID 963, SEQ ID 964, SEQ ID 965, SEQ ID 966, SEQ ID 967, SEQ ID 968, SEQ ID 969, SEQ ID 970, SEQ ID 971, SEQ ID 973, SEQ ID 974, SEQ ID 975, SEQ ID 976, SEQ ID 978, SEQ ID 982, SEQ ID 985, SEQ ID 986, SEQ ID 987, SEQ ID 991, SEQ ID 994, SEQ ID 995, SEQ ID 996, SEQ ID 997, SEQ ID 998, SEQ ID 999, SEQ ID 1000, SEQ ID 1001, SEQ ID 1002, SEQ ID 1003, SEQ ID 1004, SEQ ID 1005, SEQ ID 1006, SEQ ID 1007, SEQ ID 1008, SEQ ID 1009, SEQ ID 1010, SEQ ID 1011, SEQ ID 1012, SEQ ID 1013, SEQ ID 1014, SEQ ID 1015, SEQ ID 1016, SEQ ID 1017, SEQ ID 1018, SEQ ID 1019, SEQ ID 1020, SEQ ID 1021, SEQ ID 1022, SEQ ID 1023, SEQ ID 1024, SEQ ID 1025, SEQ ID 1026, SEQ ID 1027, SEQ ID 1028, SEQ ID 1030, SEQ ID 1031, SEQ ID 1032, SEQ ID 1033, SEQ ID 1034, SEQ ID 1035, SEQ ID 1036, SEQ ID 1037, SEQ ID 1038, SEQ ID 1039, SEQ ID 1040, SEQ ID 1041, SEQ ID 1042, SEQ ID 1043, SEQ ID 1044, SEQ ID 1045, SEQ ID 1046, SEQ ID 1047, SEQ ID 1048, SEQ ID 1049, SEQ ID 1050, SEQ ID 1051, SEQ ID 1052, SEQ ID 1053, SEQ ID 1054, SEQ ID 1055, SEQ ID 1056, SEQ ID 1057, SEQ ID 1058, SEQ ID 1059, SEQ ID 1060, SEQ ID 1061, SEQ ID 1062, SEQ ID 1063, SEQ ID 1065, SEQ ID 1066, SEQ ID 1067, SEQ ID 1068, SEQ ID 1069, SEQ ID 1070, SEQ ID 1071, SEQ ID 1072, SEQ ID 1073, SEQ ID 1074, SEQ ID 1075, SEQ ID 1076, SEQ ID 1077, SEQ ID 1078, SEQ ID 1079, SEQ ID 1080, SEQ ID 1081, SEQ ID 1082, SEQ ID 1083, SEQ ID 1084, SEQ ID 1085, SEQ ID 1086, SEQ ID 1087, SEQ ID 1088, SEQ ID 1089, SEQ ID 1090, SEQ ID 1091, SEQ ID 1092, SEQ ID 1093, SEQ ID 1094, SEQ ID 1095, SEQ ID 1098, SEQ ID 1099, SEQ ID 1100, SEQ ID 1101, SEQ ID 1102, SEQ ID 1105, SEQ ID 1106, SEQ ID 1107, SEQ ID 1108, SEQ ID 1109, SEQ ID 1110, SEQ ID 1111, SEQ ID 1112, SEQ ID 1113, SEQ ID 1114, SEQ ID 1115, SEQ ID 1116, SEQ ID 1117, SEQ ID 1118, SEQ ID 1119, SEQ ID 1120, SEQ ID 1121, SEQ ID 1122, SEQ ID 1123, SEQ ID 1124, SEQ ID 1125, SEQ ID 1126, SEQ ID 1127, SEQ ID 1128, SEQ ID 1129, SEQ ID 1130, SEQ ID 1131, SEQ ID 1132, SEQ ID 1133, SEQ ID 1134, SEQ ID 1135, SEQ ID 1136, SEQ ID 1137, SEQ ID 1138, SEQ ID 1139, SEQ ID 1140, SEQ ID 1141, SEQ ID 1142, SEQ ID 1143, SEQ ID 1144, SEQ ID 1145, SEQ ID 1146, SEQ ID 1147, SEQ ID 1187, SEQ ID 1188, SEQ ID 1189, SEQ ID 1190, SEQ ID 1191, SEQ ID 1192, SEQ ID 1193, SEQ ID 1194, SEQ ID 1195, SEQ ID 1196, SEQ ID 1197, SEQ ID 1198, SEQ ID 1199, SEQ ID 1200, SEQ ID 1201, SEQ ID 1202, SEQ ID 1203, SEQ ID 1204, SEQ ID 1205, SEQ ID 1206, SEQ ID 1207, SEQ ID 1208, SEQ ID 1209, SEQ ID 1210, SEQ ID 1211, SEQ ID 1212, SEQ ID 1213, SEQ ID 1214, SEQ ID 1215, SEQ ID 1216, SEQ ID 1217, SEQ ID 1219, SEQ ID 1220, SEQ ID 1221, SEQ ID 1222, SEQ ID 1223, SEQ ID 1224, SEQ ID 1225, SEQ ID 1226, SEQ ID 1227, SEQ ID 1230, SEQ ID 1231, SEQ ID 1232, SEQ ID 1233, SEQ ID 1234, SEQ ID 1235, SEQ ID 1236, SEQ ID 1237, SEQ ID 1238, SEQ ID 1239, SEQ ID 1240, SEQ ID 1241, SEQ ID 1242, SEQ ID 1243, SEQ ID 1244, SEQ ID 1245, SEQ ID 1246, SEQ ID 1247, SEQ ID 1248, SEQ ID 1250, SEQ ID 1251, SEQ ID 1252, SEQ ID 1253, SEQ ID 1254, SEQ ID 1255, SEQ ID 1256, SEQ ID 1257, SEQ ID 1258, SEQ ID 1259, SEQ ID 1260, SEQ ID 1261, SEQ ID 1262, SEQ ID 1263, SEQ ID 1264, SEQ ID 1265, SEQ ID 1266, SEQ ID 1267, SEQ ID 1268, SEQ ID 1269, SEQ ID 1270, SEQ ID 1271, SEQ ID 1272, SEQ ID 1273, SEQ ID 1274, SEQ ID 1275, SEQ ID 1276, SEQ ID 1277, SEQ ID 1278, SEQ ID 1279, SEQ ID 1280, SEQ ID 1281, SEQ ID 1282, SEQ ID 1283, SEQ ID 1284, SEQ ID 1285, SEQ ID 1286, SEQ ID 1287, SEQ ID 1288, SEQ ID 1289, SEQ ID 1290, SEQ ID 1291, SEQ ID 1292, SEQ ID 1293, SEQ ID 1294, SEQ ID 1295, SEQ ID 1296, SEQ ID 1297, SEQ ID 1298, SEQ ID 1299, SEQ ID 1300, SEQ ID 1301, SEQ ID 1302, SEQ ID 1303, SEQ ID 1304, SEQ ID 1306, SEQ ID 1307, SEQ ID 1308, SEQ ID 1309, SEQ ID 1310, SEQ ID 1311, SEQ ID 1312, SEQ ID 1313, SEQ ID 1314, SEQ ID 1315, SEQ ID 1316, SEQ ID 1317, SEQ ID 1318, SEQ ID 1319, SEQ ID 1320, SEQ ID 1321, SEQ ID 1322, SEQ ID 1323, SEQ ID 1325, SEQ ID 1326, SEQ ID 1327, SEQ ID 1328, SEQ ID 1329, SEQ ID 1330, SEQ ID 1332, SEQ ID 1333, SEQ ID 1335, SEQ ID 1336, SEQ ID 1337, SEQ ID 1338, SEQ ID 1339, SEQ ID 1341, SEQ ID 1342, SEQ ID 1343, SEQ ID 1344, SEQ ID 1345, SEQ ID 1346, SEQ ID 1347, SEQ ID 1348, SEQ ID 1349, SEQ ID 1350, SEQ ID 1351, SEQ ID 1352, SEQ ID 1353, SEQ ID 1354, SEQ ID 1355, SEQ ID 1356, SEQ ID 1357, SEQ ID 1425, SEQ ID 1426, SEQ ID 1427, SEQ ID 1428, SEQ ID 1429, SEQ ID 1430, SEQ ID 1431, SEQ ID 1432, SEQ ID 1433, SEQ ID 1434, SEQ ID 1435, SEQ ID 1436, SEQ ID 1437, SEQ ID 1438, SEQ ID 1440, SEQ ID 1441, SEQ ID 1442, SEQ ID 1443, SEQ ID 1444, SEQ ID 1445, SEQ ID 1446, SEQ ID 1447, SEQ ID 1448, SEQ ID 1449, SEQ ID 1450, SEQ ID 1451, SEQ ID 1452, SEQ ID 1453, SEQ ID 1454, SEQ ID 1455, SEQ ID 1456, SEQ ID 1457, SEQ ID 1458, SEQ ID 1459, SEQ ID 1460, SEQ ID 1461, SEQ ID 1462, SEQ ID 1463, SEQ ID 1464, SEQ ID 1465, SEQ ID 1466, SEQ ID 1467, SEQ ID 1469, SEQ ID 1470, SEQ ID 1471, SEQ ID 1472, SEQ ID 1474, SEQ ID 1475, SEQ ID 1476, SEQ ID 1477, SEQ ID 1478, SEQ ID 1479, SEQ ID 1480, SEQ ID 1481, SEQ ID 1482, SEQ ID 1484, SEQ ID 1485, SEQ ID 1487, SEQ ID 1488, SEQ ID 1489, SEQ ID 1491, SEQ ID 1492, SEQ ID 1493, SEQ ID 1494, SEQ ID 1495, SEQ ID 1496, SEQ ID 1497, SEQ ID 1498, SEQ ID 1499, SEQ ID 1500, SEQ ID 1501, SEQ ID 1502, SEQ ID 1503, SEQ ID 1504, SEQ ID 1505, SEQ ID 1506, SEQ ID 1507, SEQ ID 1508, SEQ ID 1509, SEQ ID 1510, SEQ ID 1511, SEQ ID 1512, SEQ ID 1513, SEQ ID 1514, SEQ ID 1515, SEQ ID 1516, SEQ ID 1517, SEQ ID 1518, SEQ ID 1519, SEQ ID 1520, SEQ ID 1521, SEQ ID 1522, SEQ ID 1523, SEQ ID 1524, SEQ ID 1525, SEQ ID 1526, SEQ ID 1527, SEQ ID 1528, SEQ ID 1529, SEQ ID 1530, SEQ ID 1531, SEQ ID 1532, SEQ ID 1533, SEQ ID 1534, SEQ ID 1535, SEQ ID 1536, SEQ ID 1537, SEQ ID 1538, SEQ ID 1539, SEQ ID 1540, SEQ ID 1541, SEQ ID 1542, SEQ ID 1543, SEQ ID 1544, SEQ ID 1545, SEQ ID 1546, SEQ ID 1547, SEQ ID 1548, SEQ ID 1549, SEQ ID 1550, SEQ ID 1551, SEQ ID 1552, SEQ ID 1553, SEQ ID 1554, SEQ ID 1555, SEQ ID 1556, SEQ ID 1557, SEQ ID 1558, SEQ ID 1559, SEQ ID 1560, SEQ ID 1561, SEQ ID 1562, SEQ ID 1563, SEQ ID 1564, SEQ ID 1565, SEQ ID 1566, SEQ ID 1567, SEQ ID 1568, SEQ ID 1569, SEQ ID 1570, SEQ ID 1571, SEQ ID 1572, SEQ ID 1573, SEQ ID 1574, SEQ ID 1575, SEQ ID 1576, SEQ ID 1577, SEQ ID 1578, SEQ ID 1579, SEQ ID 1580, SEQ ID 1581, SEQ ID 1582, SEQ ID 1583, SEQ ID 1584, SEQ ID 1585, SEQ ID 1586, SEQ ID 1587, SEQ ID 1588, SEQ ID 1589, SEQ ID 1590, SEQ ID 1591, SEQ ID 1592, SEQ ID 1593, SEQ ID 1594, SEQ ID 1595, SEQ ID 1596, SEQ ID 1597, SEQ ID 1598, SEQ ID 1599, SEQ ID 1600, SEQ ID 1601, SEQ ID 1602, SEQ ID 1603, SEQ ID 1604, SEQ ID 1605, SEQ ID 1606, SEQ ID 1607, SEQ ID 1608, SEQ ID 1609, SEQ ID 1610, SEQ ID 1611, SEQ ID 1612, SEQ ID 1613, SEQ ID 1614, SEQ ID 1615, SEQ ID 1616, SEQ ID 1617, SEQ ID 1618, SEQ ID 1620, SEQ ID 1621, SEQ ID 1622, SEQ ID 1623, SEQ ID 1624, SEQ ID 1625, SEQ ID 1626, SEQ ID 1627, SEQ ID 1628, SEQ ID 1629, SEQ ID 1630, SEQ ID 1631, SEQ ID 1632, SEQ ID 1633, SEQ ID 1634, SEQ ID 1635, SEQ ID 1636, SEQ ID 1637, SEQ ID 1638, SEQ ID 1639, SEQ ID 1640, SEQ ID 1641, SEQ ID 1642, SEQ ID 1643, SEQ ID 1644, SEQ ID 1645, SEQ ID 1647, SEQ ID 1648, SEQ ID 1649, SEQ ID 1650, SEQ ID 1651, SEQ ID 1652, SEQ ID 1654, SEQ ID 1656, SEQ ID 1657, SEQ ID 1658, SEQ ID 1659, SEQ ID 1660, SEQ ID 1661, SEQ ID 1663, SEQ ID 1664, SEQ ID 1665, SEQ ID 1666, SEQ ID 1667, SEQ ID 1668, SEQ ID 1669, SEQ ID 1670, SEQ ID 1671, SEQ ID 1672, SEQ ID 1673, SEQ ID 1674, SEQ ID 1675, SEQ ID 1676, SEQ ID 1677, SEQ ID 1678, SEQ ID 1679, SEQ ID 1680, SEQ ID 1681, SEQ ID 1682, SEQ ID 1683, SEQ ID 1684, SEQ ID 1685, SEQ ID 1686, SEQ ID 1687, SEQ ID 1688, SEQ ID 1689, SEQ ID 1690, SEQ ID 1692, SEQ ID 1693, SEQ ID 1694, SEQ ID 1695, SEQ ID 1696, SEQ ID 1697, SEQ ID 1698, SEQ ID 1699, SEQ ID 1701, SEQ ID 1703, SEQ ID 1704, SEQ ID 1705, SEQ ID 1706, SEQ ID 1707, SEQ ID 1708, SEQ ID 1709, SEQ ID 1710, SEQ ID 1711, SEQ ID 1712, SEQ ID 1714, SEQ ID 1715, SEQ ID 1716, SEQ ID 1717, SEQ ID 1718, SEQ ID 1719, SEQ ID 1720, SEQ ID 1721, SEQ ID 1722, SEQ ID 1723, SEQ ID 1724, SEQ ID 1725, SEQ ID 1726, SEQ ID 1727, SEQ ID 1728, SEQ ID 1729, SEQ ID 1730, SEQ ID 1731, SEQ ID 1732, SEQ ID 1733, SEQ ID 1734, SEQ ID 1735, SEQ ID 1736, SEQ ID 1737, SEQ ID 1738, SEQ ID 1739, SEQ ID 1740, SEQ ID 1741, SEQ ID 1742, SEQ ID 1743, SEQ ID 1762, SEQ ID 1763, SEQ ID 1764, SEQ ID 1765, SEQ ID 1766, SEQ ID 1767, SEQ ID 1768, SEQ ID 1769, SEQ ID 1770, SEQ ID 1771, SEQ ID 1772, SEQ ID 1773, SEQ ID 1774, SEQ ID 1775, SEQ ID 1776, SEQ ID 1777, SEQ ID 1778, SEQ ID 1779, SEQ ID 1780, SEQ ID 1781, SEQ ID 1782, SEQ ID 1783, SEQ ID 1784, SEQ ID 1785, SEQ ID 1786, SEQ ID 1787, SEQ ID 1788, SEQ ID 1789, SEQ ID 1790, SEQ ID 1791, SEQ ID 1792, SEQ ID 1793, SEQ ID 1794, SEQ ID 1795, SEQ ID 1796, SEQ ID 1797, SEQ ID 1798, SEQ ID 1799, SEQ ID 1800, SEQ ID 1801, SEQ ID 1802, SEQ ID 1803, SEQ ID 1804, SEQ ID 1805, SEQ ID 1806, SEQ ID 1807, SEQ ID 1808, SEQ ID 1809, SEQ ID 1810, SEQ ID 1811, SEQ ID 1812, SEQ ID 1813, SEQ ID 1814, SEQ ID 1815, SEQ ID 1816, SEQ ID 1817, SEQ ID 1818, SEQ ID 1819, SEQ ID 1820, SEQ ID 1821, SEQ ID 1822, SEQ ID 1823, SEQ ID 1824, SEQ ID 1825, SEQ ID 1826, SEQ ID 1832, SEQ ID 1833, SEQ ID 1836, SEQ ID 1837, SEQ ID 1838, SEQ ID 1839, SEQ ID 1840, SEQ ID 1858, SEQ ID 1859, SEQ ID 1860, SEQ ID 1861, SEQ ID 1862, SEQ ID 1863, SEQ ID 1865, SEQ ID 1866, SEQ ID 1868, SEQ ID 1869, SEQ ID 1873, SEQ ID 1877, SEQ ID 1880, SEQ ID 1883, SEQ ID 1884, SEQ ID 1888, SEQ ID 1889, SEQ ID 1890, SEQ ID 1893, SEQ ID 1894, SEQ ID 1895, SEQ ID 1896, SEQ ID 1897, SEQ ID 1898, SEQ ID 1899, SEQ ID 1900, SEQ ID 1902, SEQ ID 1903, SEQ ID 1904, SEQ ID 1906, SEQ ID 1907, SEQ ID 1908, SEQ ID 1910, SEQ ID 1911, SEQ ID 1913, SEQ ID 1914, SEQ ID 1915, SEQ ID 1916, SEQ ID 1918, SEQ ID 1920, SEQ ID 1921, SEQ ID 1922, SEQ ID 1924, SEQ ID 1928, SEQ ID 1929, SEQ ID 1930, SEQ ID 1932, SEQ ID 1933, SEQ ID 1938, SEQ ID 1939, SEQ ID 1940, SEQ ID 1941, SEQ ID 1943, SEQ ID 1944, SEQ ID 1945, SEQ ID 1946, SEQ ID 1948, SEQ ID 1949, SEQ ID 1950, SEQ ID 1952, SEQ ID 1953, SEQ ID 1956, SEQ ID 1957, SEQ ID 1958, SEQ ID 1960, SEQ ID 1962, SEQ ID 1964, SEQ ID 1966, SEQ ID 1967, SEQ ID 1970, SEQ ID 1971, SEQ ID 1972, SEQ ID 1973, SEQ ID 1974, SEQ ID 1975, SEQ ID 1977, SEQ ID 1979, SEQ ID 1981, SEQ ID 1982, SEQ ID 1985, SEQ ID 1986, SEQ ID 1987, SEQ ID 1988, SEQ ID 1989, SEQ ID 1993, SEQ ID 1995, SEQ ID 1996, SEQ ID 1997, SEQ ID 1998, SEQ ID 1999, SEQ ID 2000, SEQ ID 2001, SEQ ID 2002, SEQ ID 2003, SEQ ID 2004, SEQ ID 2005, SEQ ID 2008, SEQ ID 2009, SEQ ID 2010, SEQ ID 2011, SEQ ID 2013, SEQ ID 2014, SEQ ID 2015, SEQ ID 2017, SEQ ID 2019, SEQ ID 2020, SEQ ID 2021, SEQ ID 2023, SEQ ID 2026, SEQ ID 2028, SEQ ID 2031, SEQ ID 2032, SEQ ID 2033, SEQ ID 2035, SEQ ID 2036, SEQ ID 2037, SEQ ID 2038, SEQ ID 2042, SEQ ID 2044, SEQ ID 2048, SEQ ID 2050, SEQ ID 2051, SEQ ID 2052, SEQ ID 2053, SEQ ID 2054, SEQ ID 2055, SEQ ID 2056, SEQ ID 2057, SEQ ID 2058, SEQ ID 2059, SEQ ID 2060, SEQ ID 2061, SEQ ID 2062, SEQ ID 2063, SEQ ID 2064, SEQ ID 2065, SEQ ID 2066, SEQ ID 2067, SEQ ID 2068, SEQ ID 2069, SEQ ID 2070, SEQ ID 2071, SEQ ID 2072, SEQ ID 2073, SEQ ID 2074, SEQ ID 2075, SEQ ID 2076, SEQ ID 2077, SEQ ID 2078, SEQ ID 2079, SEQ ID 2080, SEQ ID 2081, SEQ ID 2082, SEQ ID 2083, SEQ ID 2084, SEQ ID 2085, SEQ ID 2086, SEQ ID 2087, SEQ ID 2088, SEQ ID 2089, SEQ ID 2090, SEQ ID 2091, SEQ ID 2092, SEQ ID 2093, SEQ ID 2094, SEQ ID 2095, SEQ ID 2096, SEQ ID 2097, SEQ ID 2098, SEQ ID 2099, SEQ ID 2101, SEQ ID 2102, SEQ ID 2103, SEQ ID 2104, SEQ ID 2105, SEQ ID 2106, SEQ ID 2107, SEQ ID 2108, SEQ ID 2109, SEQ ID 2110, SEQ ID 2111, SEQ ID 2112, SEQ ID 2113, SEQ ID 2114, SEQ ID 2115, SEQ ID 2116, SEQ ID 2117, SEQ ID 2118, SEQ ID 2119, SEQ ID 2120, SEQ ID 2121, SEQ ID 2122, SEQ ID 2123, SEQ ID 2124, SEQ ID 2125, SEQ ID 2126, SEQ ID 2127, SEQ ID 2146, SEQ ID 2147, SEQ ID 2148, SEQ ID 2149, SEQ ID 2150, SEQ ID 2151, SEQ ID 2152, SEQ ID 2153, SEQ ID 2154, SEQ ID 2155, SEQ ID 2156, SEQ ID 2157, SEQ ID 2158, SEQ ID 2159, SEQ ID 2160, SEQ ID 2161, SEQ ID 2162, SEQ ID 2163, SEQ ID 2164, SEQ ID 2165, SEQ ID 2166, SEQ ID 2167, SEQ ID 2168, SEQ ID 2169, SEQ ID 2170, SEQ ID 2171, SEQ ID 2172, SEQ ID 2173, SEQ ID 2174, SEQ ID 2175, SEQ ID 2176, SEQ ID 2177, SEQ ID 2178, SEQ ID 2179, SEQ ID 2180, SEQ ID 2181, SEQ ID 2182, SEQ ID 2183, SEQ ID 2184, SEQ ID 2185, SEQ ID 2186, SEQ ID 2187, SEQ ID 2188, SEQ ID 2189, SEQ ID 2190, SEQ ID 2191, SEQ ID 2192, SEQ ID 2193, SEQ ID 2194, SEQ ID 2195, SEQ ID 2196, SEQ ID 2197, SEQ ID 2198, SEQ ID 2199, SEQ ID 2200, SEQ ID 2201, SEQ ID 2202, SEQ ID 2203, SEQ ID 2204, SEQ ID 2205, SEQ ID 2206, SEQ ID 2207, SEQ ID 2208, SEQ ID 2209, SEQ ID 2210, SEQ ID 2211, SEQ ID 2212, SEQ ID 2213, SEQ ID 2214, SEQ ID 2216, SEQ ID 2220, SEQ ID 2222, SEQ ID 2223, SEQ ID 2224, SEQ ID 2225, SEQ ID 2239, SEQ ID 2240, SEQ ID 2241, SEQ ID 2242, SEQ ID 2243, SEQ ID 2244, SEQ ID 2245, SEQ ID 2246, SEQ ID 2247, SEQ ID 2248, SEQ ID 2249, SEQ ID 2250, SEQ ID 2251, SEQ ID 2252, SEQ ID 2253, SEQ ID 2254, SEQ ID 2255, SEQ ID 2256, SEQ ID 2257, SEQ ID 2258, SEQ ID 2259, SEQ ID 2260, SEQ ID 2261, SEQ ID 2262, SEQ ID 2263, SEQ ID 2264, SEQ ID 2265, SEQ ID 2266, SEQ ID 2267, SEQ ID 2268, SEQ ID 2269, SEQ ID 2270, SEQ ID 2271, SEQ ID 2272, SEQ ID 2273, SEQ ID 2274, SEQ ID 2275, SEQ ID 2276, SEQ ID 2277, SEQ ID 2278, SEQ ID 2279, SEQ ID 2280, SEQ ID 2281, SEQ ID 2282, SEQ ID 2283, SEQ ID 2284, SEQ ID 2285, SEQ ID 2286, SEQ ID 2287, SEQ ID 2288, SEQ ID 2289, SEQ ID 2290, SEQ ID 2291, SEQ ID 2292, SEQ ID 2293, SEQ ID 2294, SEQ ID 2295, SEQ ID 2296, SEQ ID 2297, SEQ ID 2298, SEQ ID 2299, SEQ ID 2300, SEQ ID 2301, SEQ ID 2302, SEQ ID 2303, SEQ ID 2304, SEQ ID 2305, SEQ ID 2306, SEQ ID 2307, SEQ ID 2308, SEQ ID 2309, SEQ ID 2310, SEQ ID 2311, SEQ ID 2312, SEQ ID 2313, SEQ ID 2314, SEQ ID 2315, SEQ ID 2316, SEQ ID 2317, SEQ ID 2318, SEQ ID 2319, and SEQ ID 2320.

In some embodiments, the antisense oligonucleotide progranulin agonist is selected from the group consisting of SEQ ID 693, SEQ ID 707, SEQ ID 708, SEQ ID 709, SEQ ID 710, SEQ ID 711, SEQ ID 720, SEQ ID 721, SEQ ID 723, SEQ ID 724, SEQ ID 725, SEQ ID 726, SEQ ID 727, SEQ ID 730, SEQ ID 732, SEQ ID 736, SEQ ID 737, SEQ ID 738, SEQ ID 739, SEQ ID 741, SEQ ID 743, SEQ ID 745, SEQ ID 747, SEQ ID 758, SEQ ID 759, SEQ ID 760, SEQ ID 761, SEQ ID 766, SEQ ID 775, SEQ ID 798, SEQ ID 800, SEQ ID 801, SEQ ID 802, SEQ ID 803, SEQ ID 804, SEQ ID 807, SEQ ID 812, SEQ ID 813, SEQ ID 814, SEQ ID 816, SEQ ID 818, SEQ ID 819, SEQ ID 822, SEQ ID 823, SEQ ID 824, SEQ ID 825, SEQ ID 826, SEQ ID 827, SEQ ID 828, SEQ ID 830, SEQ ID 831, SEQ ID 833, SEQ ID 835, SEQ ID 836, SEQ ID 837, SEQ ID 838, SEQ ID 839, SEQ ID 840, SEQ ID 841, SEQ ID 842, SEQ ID 843, SEQ ID 844, SEQ ID 845, SEQ ID 846, SEQ ID 847, SEQ ID 848, SEQ ID 849, SEQ ID 850, SEQ ID 854, SEQ ID 855, SEQ ID 856, SEQ ID 857, SEQ ID 859, SEQ ID 861, SEQ ID 866, SEQ ID 867, SEQ ID 868, SEQ ID 869, SEQ ID 871, SEQ ID 873, SEQ ID 874, SEQ ID 876, SEQ ID 878, SEQ ID 879, SEQ ID 880, SEQ ID 881, SEQ ID 883, SEQ ID 885, SEQ ID 887, SEQ ID 888, SEQ ID 890, SEQ ID 891, SEQ ID 892, SEQ ID 893, SEQ ID 895, SEQ ID 897, SEQ ID 906, SEQ ID 909, SEQ ID 916, SEQ ID 918, SEQ ID 926, SEQ ID 927, SEQ ID 928, SEQ ID 932, SEQ ID 933, SEQ ID 934, SEQ ID 967, SEQ ID 998, SEQ ID 1000, SEQ ID 1001, SEQ ID 1002, SEQ ID 1003, SEQ ID 1005, SEQ ID 1010, SEQ ID 1011, SEQ ID 1012, SEQ ID 1021, SEQ ID 1023, SEQ ID 1024, SEQ ID 1027, SEQ ID 1030, SEQ ID 1037, SEQ ID 1038, SEQ ID 1039, SEQ ID 1041, SEQ ID 1042, SEQ ID 1048, SEQ ID 1049, SEQ ID 1050, SEQ ID 1051, SEQ ID 1054, SEQ ID 1058, SEQ ID 1060, SEQ ID 1061, SEQ ID 1063, SEQ ID 1066, SEQ ID 1070, SEQ ID 1071, SEQ ID 1072, SEQ ID 1073, SEQ ID 1075, SEQ ID 1078, SEQ ID 1081, SEQ ID 1083, SEQ ID 1084, SEQ ID 1085, SEQ ID 1086, SEQ ID 1091, SEQ ID 1092, SEQ ID 1093, SEQ ID 1109, SEQ ID 1111, SEQ ID 1112, SEQ ID 1113, SEQ ID 1114, SEQ ID 1115, SEQ ID 1116, SEQ ID 1117, SEQ ID 1118, SEQ ID 1119, SEQ ID 1120, SEQ ID 1121, SEQ ID 1122, SEQ ID 1123, SEQ ID 1124, SEQ ID 1125, SEQ ID 1126, SEQ ID 1127, SEQ ID 1128, SEQ ID 1129, SEQ ID 1130, SEQ ID 1132, SEQ ID 1135, SEQ ID 1136, SEQ ID 1137, SEQ ID 1138, SEQ ID 1139, SEQ ID 1140, SEQ ID 1141, SEQ ID 1142, SEQ ID 1143, SEQ ID 1144, SEQ ID 1146, SEQ ID 1188, SEQ ID 1189, SEQ ID 1190, SEQ ID 1191, SEQ ID 1192, SEQ ID 1196, SEQ ID 1200, SEQ ID 1201, SEQ ID 1202, SEQ ID 1203, SEQ ID 1204, SEQ ID 1205, SEQ ID 1206, SEQ ID 1207, SEQ ID 1208, SEQ ID 1209, SEQ ID 1223, SEQ ID 1224, SEQ ID 1238, SEQ ID 1243, SEQ ID 1244, SEQ ID 1258, SEQ ID 1259, SEQ ID 1262, SEQ ID 1263, SEQ ID 1264, SEQ ID 1267, SEQ ID 1268, SEQ ID 1271, SEQ ID 1276, SEQ ID 1282, SEQ ID 1283, SEQ ID 1284, SEQ ID 1285, SEQ ID 1286, SEQ ID 1288, SEQ ID 1290, SEQ ID 1291, SEQ ID 1292, SEQ ID 1294, SEQ ID 1297, SEQ ID 1298, SEQ ID 1304, SEQ ID 1311, SEQ ID 1313, SEQ ID 1314, SEQ ID 1315, SEQ ID 1344, SEQ ID 1345, SEQ ID 1346, SEQ ID 1347, SEQ ID 1348, SEQ ID 1349, SEQ ID 1352, SEQ ID 1355, SEQ ID 1357, SEQ ID 1425, SEQ ID 1426, SEQ ID 1427, SEQ ID 1428, SEQ ID 1430, SEQ ID 1431, SEQ ID 1432, SEQ ID 1433, SEQ ID 1434, SEQ ID 1435, SEQ ID 1436, SEQ ID 1437, SEQ ID 1438, SEQ ID 1440, SEQ ID 1441, SEQ ID 1442, SEQ ID 1443, SEQ ID 1444, SEQ ID 1445, SEQ ID 1446, SEQ ID 1447, SEQ ID 1448, SEQ ID 1449, SEQ ID 1450, SEQ ID 1451, SEQ ID 1454, SEQ ID 1455, SEQ ID 1456, SEQ ID 1457, SEQ ID 1460, SEQ ID 1461, SEQ ID 1462, SEQ ID 1463, SEQ ID 1464, SEQ ID 1467, SEQ ID 1469, SEQ ID 1474, SEQ ID 1478, SEQ ID 1480, SEQ ID 1482, SEQ ID 1488, SEQ ID 1492, SEQ ID 1493, SEQ ID 1497, SEQ ID 1498, SEQ ID 1505, SEQ ID 1506, SEQ ID 1507, SEQ ID 1509, SEQ ID 1510, SEQ ID 1512, SEQ ID 1513, SEQ ID 1514, SEQ ID 1515, SEQ ID 1517, SEQ ID 1520, SEQ ID 1524, SEQ ID 1525, SEQ ID 1528, SEQ ID 1529, SEQ ID 1530, SEQ ID 1531, SEQ ID 1532, SEQ ID 1533, SEQ ID 1534, SEQ ID 1535, SEQ ID 1536, SEQ ID 1537, SEQ ID 1538, SEQ ID 1539, SEQ ID 1540, SEQ ID 1541, SEQ ID 1542, SEQ ID 1544, SEQ ID 1545, SEQ ID 1546, SEQ ID 1547, SEQ ID 1548, SEQ ID 1549, SEQ ID 1550, SEQ ID 1551, SEQ ID 1552, SEQ ID 1553, SEQ ID 1554, SEQ ID 1555, SEQ ID 1556, SEQ ID 1558, SEQ ID 1560, SEQ ID 1563, SEQ ID 1565, SEQ ID 1568, SEQ ID 1569, SEQ ID 1575, SEQ ID 1577, SEQ ID 1578, SEQ ID 1579, SEQ ID 1582, SEQ ID 1583, SEQ ID 1584, SEQ ID 1585, SEQ ID 1586, SEQ ID 1587, SEQ ID 1588, SEQ ID 1589, SEQ ID 1590, SEQ ID 1591, SEQ ID 1593, SEQ ID 1594, SEQ ID 1595, SEQ ID 1596, SEQ ID 1599, SEQ ID 1608, SEQ ID 1609, SEQ ID 1610, SEQ ID 1611, SEQ ID 1612, SEQ ID 1613, SEQ ID 1614, SEQ ID 1615, SEQ ID 1616, SEQ ID 1617, SEQ ID 1618, SEQ ID 1620, SEQ ID 1621, SEQ ID 1622, SEQ ID 1623, SEQ ID 1624, SEQ ID 1626, SEQ ID 1630, SEQ ID 1631, SEQ ID 1633, SEQ ID 1635, SEQ ID 1637, SEQ ID 1638, SEQ ID 1639, SEQ ID 1643, SEQ ID 1644, SEQ ID 1645, SEQ ID 1648, SEQ ID 1649, SEQ ID 1651, SEQ ID 1658, SEQ ID 1667, SEQ ID 1669, SEQ ID 1677, SEQ ID 1679, SEQ ID 1681, SEQ ID 1684, SEQ ID 1685, SEQ ID 1686, SEQ ID 1688, SEQ ID 1689, SEQ ID 1690, SEQ ID 1692, SEQ ID 1704, SEQ ID 1707, SEQ ID 1708, SEQ ID 1709, SEQ ID 1710, SEQ ID 1711, SEQ ID 1712, SEQ ID 1714, SEQ ID 1715, SEQ ID 1717, SEQ ID 1718, SEQ ID 1719, SEQ ID 1720, SEQ ID 1721, SEQ ID 1722, SEQ ID 1723, SEQ ID 1724, SEQ ID 1725, SEQ ID 1726, SEQ ID 1727, SEQ ID 1728, SEQ ID 1731, SEQ ID 1732, SEQ ID 1733, SEQ ID 1734, SEQ ID 1735, SEQ ID 1736, SEQ ID 1737, SEQ ID 1738, SEQ ID 1741, SEQ ID 1742, SEQ ID 1762, SEQ ID 1764, SEQ ID 1765, SEQ ID 1766, SEQ ID 1767, SEQ ID 1768, SEQ ID 1769, SEQ ID 1770, SEQ ID 1771, SEQ ID 1773, SEQ ID 1775, SEQ ID 1776, SEQ ID 1779, SEQ ID 1780, SEQ ID 1781, SEQ ID 1782, SEQ ID 1783, SEQ ID 1784, SEQ ID 1785, SEQ ID 1786, SEQ ID 1787, SEQ ID 1789, SEQ ID 1791, SEQ ID 1792, SEQ ID 1794, SEQ ID 1795, SEQ ID 1796, SEQ ID 1800, SEQ ID 1801, SEQ ID 1802, SEQ ID 1804, SEQ ID 1805, SEQ ID 1806, SEQ ID 1807, SEQ ID 1808, SEQ ID 1809, SEQ ID 1811, SEQ ID 1812, SEQ ID 1813, SEQ ID 1814, SEQ ID 1815, SEQ ID 1816, SEQ ID 1817, SEQ ID 1818, SEQ ID 1819, SEQ ID 1820, SEQ ID 1821, SEQ ID 1822, SEQ ID 1823, SEQ ID 1824, SEQ ID 1832, SEQ ID 1833, SEQ ID 1838, SEQ ID 1839, SEQ ID 1840, SEQ ID 1862, SEQ ID 1866, SEQ ID 1868, SEQ ID 1873, SEQ ID 1877, SEQ ID 1883, SEQ ID 1884, SEQ ID 1888, SEQ ID 1889, SEQ ID 1893, SEQ ID 1894, SEQ ID 1928, SEQ ID 1929, SEQ ID 1933, SEQ ID 1938, SEQ ID 1939, SEQ ID 1940, SEQ ID 1941, SEQ ID 1943, SEQ ID 1944, SEQ ID 1948, SEQ ID 1950, SEQ ID 1952, SEQ ID 1956, SEQ ID 1966, SEQ ID 1985, SEQ ID 1986, SEQ ID 1996, SEQ ID 1997, SEQ ID 1998, SEQ ID 1999, SEQ ID 2000, SEQ ID 2005, SEQ ID 2013, SEQ ID 2015, SEQ ID 2020, SEQ ID 2023, SEQ ID 2026, SEQ ID 2028, SEQ ID 2031, SEQ ID 2032, SEQ ID 2033, SEQ ID 2042, SEQ ID 2048, SEQ ID 2052, SEQ ID 2053, SEQ ID 2055, SEQ ID 2056, SEQ ID 2057, SEQ ID 2058, SEQ ID 2059, SEQ ID 2060, SEQ ID 2061, SEQ ID 2063, SEQ ID 2065, SEQ ID 2066, SEQ ID 2067, SEQ ID 2068, SEQ ID 2070, SEQ ID 2072, SEQ ID 2073, SEQ ID 2075, SEQ ID 2076, SEQ ID 2079, SEQ ID 2080, SEQ ID 2081, SEQ ID 2082, SEQ ID 2083, SEQ ID 2084, SEQ ID 2085, SEQ ID 2086, SEQ ID 2087, SEQ ID 2088, SEQ ID 2089, SEQ ID 2090, SEQ ID 2091, SEQ ID 2092, SEQ ID 2093, SEQ ID 2094, SEQ ID 2095, SEQ ID 2097, SEQ ID 2116, SEQ ID 2119, SEQ ID 2120, SEQ ID 2121, SEQ ID 2122, SEQ ID 2123, SEQ ID 2124, SEQ ID 2125, SEQ ID 2126, SEQ ID 2127, SEQ ID 2146, SEQ ID 2147, SEQ ID 2148, SEQ ID 2158, SEQ ID 2160, SEQ ID 2162, SEQ ID 2163, SEQ ID 2165, SEQ ID 2166, SEQ ID 2167, SEQ ID 2168, SEQ ID 2169, SEQ ID 2170, SEQ ID 2171, SEQ ID 2172, SEQ ID 2173, SEQ ID 2174, SEQ ID 2175, SEQ ID 2176, SEQ ID 2177, SEQ ID 2181, SEQ ID 2182, SEQ ID 2183, SEQ ID 2184, SEQ ID 2185, SEQ ID 2186, SEQ ID 2187, SEQ ID 2193, SEQ ID 2194, SEQ ID 2195, SEQ ID 2196, SEQ ID 2197, SEQ ID 2198, SEQ ID 2199, SEQ ID 2200, SEQ ID 2202, SEQ ID 2203, SEQ ID 2204, SEQ ID 2206, SEQ ID 2208, SEQ ID 2209, SEQ ID 2210, SEQ ID 2211, SEQ ID 2212, SEQ ID 2213, SEQ ID 2214, SEQ ID 2216, SEQ ID 2222, SEQ ID 2224, SEQ ID 2239, SEQ ID 2240, SEQ ID 2242, SEQ ID 2243, SEQ ID 2244, SEQ ID 2245, SEQ ID 2246, SEQ ID 2247, SEQ ID 2248, SEQ ID 2251, SEQ ID 2252, SEQ ID 2253, SEQ ID 2254, SEQ ID 2255, SEQ ID 2256, SEQ ID 2257, SEQ ID 2258, SEQ ID 2259, SEQ ID 2260, SEQ ID 2261, SEQ ID 2262, SEQ ID 2263, SEQ ID 2264, SEQ ID 2265, SEQ ID 2266, SEQ ID 2267, SEQ ID 2268, SEQ ID 2269, SEQ ID 2280, SEQ ID 2281, SEQ ID 2282, SEQ ID 2283, SEQ ID 2284, SEQ ID 2285, SEQ ID 2294, SEQ ID 2295, SEQ ID 2302, SEQ ID 2307, SEQ ID 2308, SEQ ID 2309, SEQ ID 2310, SEQ ID 2311, SEQ ID 2312, SEQ ID 2316, SEQ ID 2317, SEQ ID 2318, SEQ ID 2319, and SEQ ID 2320.

The invention provides for a conjugate comprising the antisense oligonucleotide progranulin agonist according to the invention, and at least one conjugate moiety covalently attached to said antisense oligonucleotide progranulin agonist.

The invention provides an antisense oligonucleotide progranulin agonist covalently attached to at least one conjugate moiety.

The invention provides for a pharmaceutically acceptable salt of the antisense oligonucleotide progranulin agonist according to the invention, or the conjugate according to the invention.

The invention provides for an antisense oligonucleotide progranulin agonist according to the invention wherein the antisense oligonucleotide progranulin agonist is in the form of a pharmaceutically acceptable salt. In some embodiments the pharmaceutically acceptable salt may be a sodium salt or a potassium salt.

The invention provides for a pharmaceutically acceptable sodium salt of the antisense oligonucleotide progranulin agonist according to the invention, or the conjugate according to the invention.

The invention provides for a pharmaceutically acceptable potassium salt of the antisense oligonucleotide progranulin agonist according to the invention, or the conjugate according to the invention.

The invention provides for a pharmaceutical composition comprising the antisense oligonucleotide progranulin agonist of the invention, or the conjugate of the invention, and a pharmaceutically acceptable diluent, solvent, carrier, salt and/or adjuvant.

The invention provides for a pharmaceutical composition according to the invention, wherein the pharmaceutical composition comprises the antisense oligonucleotide progranulin agonist of the invention or the conjugate of the invention, or the pharmaceutically acceptable salt of the invention; and an aqueous diluent or solvent.

The invention provides for a solution, such as a phosphate buffered saline solution of the antisense oligonucleotide progranulin agonist of the invention, or the conjugate of the invention, or the pharmaceutically acceptable salt of the invention. Suitably the solution, such as phosphate buffered saline solution, of the invention, is a sterile solution.

The invention provides for a method for enhancing the expression of progranulin in a cell which is expressing progranulin, said method comprising administering an antisense oligonucleotide progranulin agonist of the invention or the conjugate of the invention, or the salt according to the invention, or the pharmaceutical composition according to the invention in an effective amount to said cell. In some embodiments the method is an in vitro method. In some embodiments the method is an in vivo method.

In some embodiments, the cell is either a human cell or a mammalian cell.

The invention provides for a method for treating or preventing neurological disease, comprising administering a therapeutically or prophylactically effective amount of an antisense oligonucleotide progranulin agonist of the invention or the conjugate of the invention, or the salt of the invention, or the pharmaceutical composition of the invention to a subject suffering from or susceptible to neurological disease. In one embodiment the neurological disease may be a TDP-43 pathology.

The invention provides for a method for treating progranulin haploinsufficiency disease, comprising administering a therapeutically or prophylactically effective amount of an antisense oligonucleotide progranulin agonist of the invention or the conjugate of the invention, or the salt of the invention, or the pharmaceutical composition of the invention to a subject suffering from progranulin haploinsufficiency or a related disorder.

The invention provides for an antisense oligonucleotide progranulin agonist, for use as a medicament.

The invention provides for an antisense oligonucleotide progranulin agonist, for use in therapy.

The invention provides for the antisense oligonucleotide progranulin agonist of the invention or the conjugate of the invention, or the salt of the invention, or the pharmaceutical composition of the invention, for use as a medicament.

The invention provides an antisense oligonucleotide progranulin agonist of the invention or the conjugate of the invention, or the salt according to the invention, or the pharmaceutical composition according to the invention for use in therapy.

The invention provides for an antisense oligonucleotide progranulin agonist of the invention or the conjugate according to the invention, or the salt according to the invention, or the pharmaceutical composition according to the invention for use in the treatment of a neurological disease. In one embodiment the neurological disease may be a TDP-43 pathology.

The invention provides for an antisense oligonucleotide progranulin agonist of the invention or the conjugate according to the invention, or the salt according to the invention, or the pharmaceutical composition according to the invention for use in the treatment of progranulin haploinsufficiency, or a related disorder.

The invention provides for the use of an antisense oligonucleotide progranulin agonist of the invention or the conjugate according to the invention, or the salt according to the invention, or the pharmaceutical composition according to the invention, for the preparation of a medicament for treatment or prevention of a neurological disease In one embodiment the neurological disease may be a TDP-43 pathology.

The invention provides for the use of the antisense oligonucleotide progranulin agonist of the invention or the conjugate according to the invention, or the salt according to the invention, or the pharmaceutical composition according to the invention, for the preparation of a medicament for treatment of progranulin haploinsufficiency or a related disorder.

In some embodiments the method or use of the invention is for the treatment of fronto temporal dementia (FTD), neuropathologic frontotemporal lobar degeneration or neuroinflammation. In other embodiments the method or use of the invention is for the treatment of amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, Autism, Hippocampal sclerosis dementia, Down syndrome, Huntington's disease, polyglutamine diseases, spinocerebellar ataxia 3, myopathies or Chronic Traumatic Encephalopathy.

In one aspect the invention includes an oligonucleotide progranulin agonist having the structure:

embedded image

The invention also includes an antisense oligonucleotide progranulin agonist wherein the oligonucleotide is the oligonucleotide compound TgGccAggGatCagGG (SEQ ID NO: 106) wherein capital letters represent beta-D-oxy LNA nucleosides, lowercase letters represent DNA nucleosides, all LNA C are 5-methyl cytosine, and all internucleoside linkages are phosphorothioate internucleoside linkages.

BRIEF DESCRIPTION OF FIGURES

FIG. 1 shows progranulin expression levels in H4 neuroglioma cells following 5 days of treatment with 16-mer oligos targeting the progranulin 5′ UTR uORF region. Progranulin expression levels were evaluated in media after dilution 1:8 by ELISA from Abcam (ab252364).

FIG. 2 shows localization of compounds #105, #106, #110 and #114 to the 5′ UTR of the proganulin mature mRNA transcript, targeting the uORF region.

FIGS. 3 and 4 show progranulin expression levels in H4 neuroglioma cells following 5 days of treatment with 16-mer oligos targeting 5′ UTR uORF region. Progranulin expression levels were evaluated in cell lysate (RIPA lysis and extraction buffer from Pierce cat. No. 89900) using the WES platform (ProteinSimple) and GRN antibody Invitrogen PA5-27275 diluted 1:25 and HPRT1 antibody ab109021 (Abcam) diluted 1:50.

FIG. 5 shows the level of progranulin expression in hiPSC derived micoglia following 5 days of treatment with Compound #106. Progranulin expression levels were evaluated in media after dilution 1:8 by ELISA from Abcam (ab252364).

FIG. 6 shows progranulin expression levels in H4 neuroglioma cells following 5 days of treatment with 18-mer oligos targeting the progranulin 5′ UTR uORF region. Progranulin expression levels were evaluated in media after dilution 1:8 by ELISA from Abcam (ab252364).

FIG. 7 shows the structure of Compound ID #106 (SEQ ID NO 106).

FIG. 8 shows progranulin expression in H4 neuroglioma cells following treatment with Compound #106, Compound #106 full 2′MOE, and Compound #106 full 2′oMe.

FIG. 9 shows heat maps indicating genes upregulated and down regulated relative to PBS control treated cells. Left is compound #106, middle is Compound #106 full 2′oMe and right is Compound #106 full 2′MOE.

FIG. 10 is a plot showing the position of oligos within the progranulin precursor-mRNA (pre-mRNA) sequence (SEQ ID NO 3949) relative to the activity of the oligo. Oligos complementary to exon-exon junctions are plotted downstream of the schematic figure of the pre-mRNA

DEFINITIONS

Progranulin Agonist

The term “progranulin agonist” as used herein refers to a compound which is capable of enhancing the expression of progranulin transcripts and/or protein in a cell which is expressing progranulin.

Tdp-43 Pathologies

A TDP-43 pathology is a disease which is associated with reduced or aberrant expression of TDP-43, often associated with an increase in cytoplasmic TDP-43, particularly hyper-phosphorylated and ubiquitinated TDP-43.

Diseases associated with TDP-43 pathology include amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Alzheimer's disease, Parkinson's disease, Autism, Hippocampal sclerosis dementia, Down syndrome, Huntington's disease, polyglutamine diseases, such as spinocerebellar ataxia 3, myopathies and Chronic Traumatic Encephalopathy.

Oligonucleotide

The term “oligonucleotide” as used herein is defined as it is generally understood by the skilled person as a molecule comprising two or more covalently linked nucleosides. Such covalently bound nucleosides may also be referred to as nucleic acid molecules or oligomers.

Oligonucleotides are commonly made in the laboratory by solid-phase chemical synthesis followed by purification and isolation. When referring to a sequence of the oligonucleotide, reference is made to the sequence or order of nucleobase moieties, or modifications thereof, of the covalently linked nucleotides or nucleosides. The oligonucleotides of the invention are man-made, and are chemically synthesized, and are typically purified or isolated. The oligonucleotides of the invention may comprise one or more modified nucleosides such as 2′ sugar modified nucleosides. The oligonucleotides of the invention may comprise one or more modified internucleoside linkages, such as one or more phosphorothioate internucleoside linkages.

Antisense Oligonucleotides

The term “antisense oligonucleotide” as used herein is defined as an oligonucleotide capable of modulating expression of a target gene by hybridizing to a target nucleic acid, in particular to a contiguous sequence on a target nucleic acid. Antisense oligonucleotides are not essentially double stranded and are therefore not siRNAs or shRNAs. The antisense oligonucleotides of the present invention may be single stranded. It is understood that single stranded oligonucleotides of the present invention can form hairpins or intermolecular duplex structures (duplex between two molecules of the same oligonucleotide), as long as the degree of intra or inter self-complementarity is less than approximately 50% across of the full length of the oligonucleotide.

In some embodiments, the single stranded antisense oligonucleotides of the invention may not contain RNA nucleosides.

Advantageously, the antisense oligonucleotides of the invention comprise one or more modified nucleosides or nucleotides, such as 2′ sugar modified nucleosides. Furthermore, in some antisense oligonucleotides of the invention, it may be advantageous that the nucleosides which are not modified are DNA nucleosides.

Contiguous Nucleotide Sequence

The term “contiguous nucleotide sequence” refers to the region of the oligonucleotide which is complementary to a target nucleic acid, which may be or may comprise an oligonucleotide motif sequence. The term is used interchangeably herein with the term “contiguous nucleobase sequence”. In some embodiments all the nucleosides of the oligonucleotide constitute the contiguous nucleotide sequence. The contiguous nucleotide sequence is the sequence of nucleotides in the oligonucleotide of the invention which are complementary to, and in some instances fully complementary to, the target nucleic acid or target sequence, or target site sequence.

In some embodiments the target sequence is SEQ ID NO 2.

SEQ ID NO 2:

TAGCCCTGATCCCTGGCCAATGGAAACTGAGGTAGG

In some embodiments the target sequence is selected from the group consisting of SEQ ID NO 343-682.

In some embodiments the target sequence is nucleotides 38-246 of SEQ ID NO 1.

In some embodiments the target sequence is selected from the group consisting of SEQ ID NO 568, SEQ ID NO 571, SEQ ID NO 575, SEQ ID NO 576, SEQ ID NO 577, SEQ ID NO 578, SEQ ID NO 584 & SEQ ID NO 586.

In some embodiments the target sequence is SEQ ID NO 683.

SEQ ID NO 683 =

TGGCCAATGGAAACTGAGGTAGG

In some embodiments the target sequence is SEQ ID NO 684.

SEQ ID NO 684 =

CCCTAGCACCTCCCCCTAACCAAATTCTCCCTG

In some embodiments the target sequence is SEQ ID NO 685.

SEQ ID NO 685 =

CCCATTCTGAGCTCCCCATCA

In some embodiments the target sequence is SEQ ID NO 686.

SEQ ID NO 686 =

AGGGGGTTGTGGCAAAAGCCA

In some embodiments the target sequence is SEQ ID NO 687.

SEQ ID NO 687 =

CCATCCCCTCCCCGTTTCAGT

In some embodiments the target sequence is SEQ ID NO 688.

SEQ ID NO 688 =

ATCCACAGGGGTGTTTGT

In some embodiments the target sequence is SEQ ID NO 689.

SEQ ID NO 689 =

TAAGTAGCCAATGGGAGCGGGTAGCCCTGATCCCTGGCCAATGGAAACT

GAGGTAGG

SEQ ID NO 689 is in the human progranulin mature mRNA 5′ UTR from position 119 to 158 according to RefSeq NM_002087 (SEQ ID NO 1), as targeted by SEQ ID NOs 207 to 246 and identified herein as an advantageous region to target for progranulin agonist activity.

In some embodiments the target sequence is nucleotides 2039-2346 of SEQ ID NO 1.

In some embodiments the target sequence is selected from the group consisting of SEQ ID NO 684, SEQ ID NO 685, SEQ ID NO 683, SEQ ID NO 686, SEQ ID NO 687, and SEQ ID NO 688.

In some embodiments the target sequence is selected from the group consisting of SEQ ID NO 607, SEQ ID NO 608, SEQ ID NO 609, SEQ ID NO 610, SEQ ID NO 611, SEQ ID NO 612, SEQ ID NO 619, SEQ ID NO 620, SEQ ID NO 633, SEQ ID NO 640, SEQ ID NO 641, SEQ ID NO 645, SEQ ID NO 651, and SEQ ID NO 652.

In some embodiments the target sequence is selected from the group consisting of SEQ ID NO 2040-3386.

In some embodiments the target sequence is selected from the group consisting of SEQ ID 2321, SEQ ID 2322, SEQ ID 2324, SEQ ID 2328, SEQ ID 2329, SEQ ID 2331, SEQ ID 2334, SEQ ID 2335, SEQ ID 2336, SEQ ID 2337, SEQ ID 2338, SEQ ID 2339, SEQ ID 2340, SEQ ID 2341, SEQ ID 2342, SEQ ID 2345, SEQ ID 2346, SEQ ID 2347, SEQ ID 2348, SEQ ID 2349, SEQ ID 2350, SEQ ID 2351, SEQ ID 2352, SEQ ID 2353, SEQ ID 2354, SEQ ID 2355, SEQ ID 2356, SEQ ID 2357, SEQ ID 2358, SEQ ID 2359, SEQ ID 2360, SEQ ID 2361, SEQ ID 2362, SEQ ID 2364, SEQ ID 2365, SEQ ID 2366, SEQ ID 2367, SEQ ID 2368, SEQ ID 2369, SEQ ID 2370, SEQ ID 2371, SEQ ID 2372, SEQ ID 2373, SEQ ID 2374, SEQ ID 2375, SEQ ID 2376, SEQ ID 2377, SEQ ID 2378, SEQ ID 2379, SEQ ID 2380, SEQ ID 2381, SEQ ID 2384, SEQ ID 2386, SEQ ID 2387, SEQ ID 2388, SEQ ID 2389, SEQ ID 2390, SEQ ID 2392, SEQ ID 2393, SEQ ID 2394, SEQ ID 2395, SEQ ID 2396, SEQ ID 2397, SEQ ID 2398, SEQ ID 2399, SEQ ID 2400, SEQ ID 2401, SEQ ID 2403, SEQ ID 2404, SEQ ID 2405, SEQ ID 2406, SEQ ID 2407, SEQ ID 2408, SEQ ID 2410, SEQ ID 2411, SEQ ID 2413, SEQ ID 2414, SEQ ID 2415, SEQ ID 2416, SEQ ID 2418, SEQ ID 2419, SEQ ID 2421, SEQ ID 2424, SEQ ID 2425, SEQ ID 2426, SEQ ID 2427, SEQ ID 2428, SEQ ID 2429, SEQ ID 2430, SEQ ID 2431, SEQ ID 2432, SEQ ID 2433, SEQ ID 2434, SEQ ID 2435, SEQ ID 2436, SEQ ID 2437, SEQ ID 2438, SEQ ID 2439, SEQ ID 2440, SEQ ID 2441, SEQ ID 2442, SEQ ID 2443, SEQ ID 2444, SEQ ID 2445, SEQ ID 2446, SEQ ID 2447, SEQ ID 2448, SEQ ID 2449, SEQ ID 2450, SEQ ID 2451, SEQ ID 2452, SEQ ID 2453, SEQ ID 2454, SEQ ID 2455, SEQ ID 2456, SEQ ID 2457, SEQ ID 2458, SEQ ID 2459, SEQ ID 2460, SEQ ID 2461, SEQ ID 2462, SEQ ID 2463, SEQ ID 2464, SEQ ID 2465, SEQ ID 2466, SEQ ID 2467, SEQ ID 2468, SEQ ID 2469, SEQ ID 2470, SEQ ID 2471, SEQ ID 2472, SEQ ID 2473, SEQ ID 2474, SEQ ID 2475, SEQ ID 2476, SEQ ID 2477, SEQ ID 2478, SEQ ID 2479, SEQ ID 2481, SEQ ID 2482, SEQ ID 2483, SEQ ID 2484, SEQ ID 2485, SEQ ID 2487, SEQ ID 2489, SEQ ID 2490, SEQ ID 2491, SEQ ID 2492, SEQ ID 2493, SEQ ID 2494, SEQ ID 2495, SEQ ID 2496, SEQ ID 2497, SEQ ID 2498, SEQ ID 2499, SEQ ID 2501, SEQ ID 2502, SEQ ID 2503, SEQ ID 2504, SEQ ID 2505, SEQ ID 2506, SEQ ID 2507, SEQ ID 2508, SEQ ID 2509, SEQ ID 2510, SEQ ID 2511, SEQ ID 2512, SEQ ID 2513, SEQ ID 2514, SEQ ID 2515, SEQ ID 2516, SEQ ID 2518, SEQ ID 2519, SEQ ID 2520, SEQ ID 2521, SEQ ID 2522, SEQ ID 2523, SEQ ID 2524, SEQ ID 2525, SEQ ID 2526, SEQ ID 2527, SEQ ID 2528, SEQ ID 2531, SEQ ID 2533, SEQ ID 2534, SEQ ID 2535, SEQ ID 2536, SEQ ID 2537, SEQ ID 2538, SEQ ID 2540, SEQ ID 2541, SEQ ID 2542, SEQ ID 2544, SEQ ID 2546, SEQ ID 2547, SEQ ID 2549, SEQ ID 2550, SEQ ID 2551, SEQ ID 2553, SEQ ID 2554, SEQ ID 2555, SEQ ID 2556, SEQ ID 2557, SEQ ID 2560, SEQ ID 2561, SEQ ID 2562, SEQ ID 2563, SEQ ID 2565, SEQ ID 2566, SEQ ID 2567, SEQ ID 2572, SEQ ID 2573, SEQ ID 2574, SEQ ID 2575, SEQ ID 2576, SEQ ID 2577, SEQ ID 2578, SEQ ID 2579, SEQ ID 2580, SEQ ID 2581, SEQ ID 2582, SEQ ID 2583, SEQ ID 2584, SEQ ID 2585, SEQ ID 2586, SEQ ID 2588, SEQ ID 2589, SEQ ID 2590, SEQ ID 2591, SEQ ID 2592, SEQ ID 2593, SEQ ID 2594, SEQ ID 2595, SEQ ID 2596, SEQ ID 2597, SEQ ID 2598, SEQ ID 2599, SEQ ID 2601, SEQ ID 2602, SEQ ID 2603, SEQ ID 2604, SEQ ID 2606, SEQ ID 2610, SEQ ID 2613, SEQ ID 2614, SEQ ID 2615, SEQ ID 2619, SEQ ID 2622, SEQ ID 2623, SEQ ID 2624, SEQ ID 2625, SEQ ID 2626, SEQ ID 2627, SEQ ID 2628, SEQ ID 2629, SEQ ID 2630, SEQ ID 2631, SEQ ID 2632, SEQ ID 2633, SEQ ID 2634, SEQ ID 2635, SEQ ID 2636, SEQ ID 2637, SEQ ID 2638, SEQ ID 2639, SEQ ID 2640, SEQ ID 2641, SEQ ID 2642, SEQ ID 2643, SEQ ID 2644, SEQ ID 2645, SEQ ID 2646, SEQ ID 2647, SEQ ID 2648, SEQ ID 2649, SEQ ID 2650, SEQ ID 2651, SEQ ID 2652, SEQ ID 2653, SEQ ID 2654, SEQ ID 2655, SEQ ID 2656, SEQ ID 2658, SEQ ID 2659, SEQ ID 2660, SEQ ID 2661, SEQ ID 2662, SEQ ID 2663, SEQ ID 2664, SEQ ID 2665, SEQ ID 2666, SEQ ID 2667, SEQ ID 2668, SEQ ID 2669, SEQ ID 2670, SEQ ID 2671, SEQ ID 2672, SEQ ID 2673, SEQ ID 2674, SEQ ID 2675, SEQ ID 2676, SEQ ID 2677, SEQ ID 2678, SEQ ID 2679, SEQ ID 2680, SEQ ID 2681, SEQ ID 2682, SEQ ID 2683, SEQ ID 2684, SEQ ID 2685, SEQ ID 2686, SEQ ID 2687, SEQ ID 2688, SEQ ID 2689, SEQ ID 2690, SEQ ID 2691, SEQ ID 2693, SEQ ID 2694, SEQ ID 2695, SEQ ID 2696, SEQ ID 2697, SEQ ID 2698, SEQ ID 2699, SEQ ID 2700, SEQ ID 2701, SEQ ID 2702, SEQ ID 2703, SEQ ID 2704, SEQ ID 2705, SEQ ID 2706, SEQ ID 2707, SEQ ID 2708, SEQ ID 2709, SEQ ID 2710, SEQ ID 2711, SEQ ID 2712, SEQ ID 2713, SEQ ID 2714, SEQ ID 2715, SEQ ID 2716, SEQ ID 2717, SEQ ID 2718, SEQ ID 2719, SEQ ID 2720, SEQ ID 2721, SEQ ID 2722, SEQ ID 2723, SEQ ID 2726, SEQ ID 2727, SEQ ID 2728, SEQ ID 2729, SEQ ID 2730, SEQ ID 2733, SEQ ID 2734, SEQ ID 2735, SEQ ID 2736, SEQ ID 2737, SEQ ID 2738, SEQ ID 2739, SEQ ID 2740, SEQ ID 2741, SEQ ID 2742, SEQ ID 2743, SEQ ID 2744, SEQ ID 2745, SEQ ID 2746, SEQ ID 2747, SEQ ID 2748, SEQ ID 2749, SEQ ID 2750, SEQ ID 2751, SEQ ID 2752, SEQ ID 2753, SEQ ID 2754, SEQ ID 2755, SEQ ID 2756, SEQ ID 2757, SEQ ID 2758, SEQ ID 2759, SEQ ID 2760, SEQ ID 2761, SEQ ID 2762, SEQ ID 2763, SEQ ID 2764, SEQ ID 2765, SEQ ID 2766, SEQ ID 2767, SEQ ID 2768, SEQ ID 2769, SEQ ID 2770, SEQ ID 2771, SEQ ID 2772, SEQ ID 2773, SEQ ID 2774, SEQ ID 2775, SEQ ID 2815, SEQ ID 2816, SEQ ID 2817, SEQ ID 2818, SEQ ID 2819, SEQ ID 2820, SEQ ID 2821, SEQ ID 2822, SEQ ID 2823, SEQ ID 2824, SEQ ID 2825, SEQ ID 2826, SEQ ID 2827, SEQ ID 2828, SEQ ID 2829, SEQ ID 2830, SEQ ID 2831, SEQ ID 2832, SEQ ID 2833, SEQ ID 2834, SEQ ID 2835, SEQ ID 2836, SEQ ID 2837, SEQ ID 2838, SEQ ID 2839, SEQ ID 2840, SEQ ID 2841, SEQ ID 2842, SEQ ID 2843, SEQ ID 2844, SEQ ID 2845, SEQ ID 2847, SEQ ID 2848, SEQ ID 2849, SEQ ID 2850, SEQ ID 2851, SEQ ID 2852, SEQ ID 2853, SEQ ID 2854, SEQ ID 2855, SEQ ID 2858, SEQ ID 2859, SEQ ID 2860, SEQ ID 2861, SEQ ID 2862, SEQ ID 2863, SEQ ID 2864, SEQ ID 2865, SEQ ID 2866, SEQ ID 2867, SEQ ID 2868, SEQ ID 2869, SEQ ID 2870, SEQ ID 2871, SEQ ID 2872, SEQ ID 2873, SEQ ID 2874, SEQ ID 2875, SEQ ID 2876, SEQ ID 2878, SEQ ID 2879, SEQ ID 2880, SEQ ID 2881, SEQ ID 2882, SEQ ID 2883, SEQ ID 2884, SEQ ID 2885, SEQ ID 2886, SEQ ID 2887, SEQ ID 2888, SEQ ID 2889, SEQ ID 2890, SEQ ID 2891, SEQ ID 2892, SEQ ID 2893, SEQ ID 2894, SEQ ID 2895, SEQ ID 2896, SEQ ID 2897, SEQ ID 2898, SEQ ID 2899, SEQ ID 2900, SEQ ID 2901, SEQ ID 2902, SEQ ID 2903, SEQ ID 2904, SEQ ID 2905, SEQ ID 2906, SEQ ID 2907, SEQ ID 2908, SEQ ID 2909, SEQ ID 2910, SEQ ID 2911, SEQ ID 2912, SEQ ID 2913, SEQ ID 2914, SEQ ID 2915, SEQ ID 2916, SEQ ID 2917, SEQ ID 2918, SEQ ID 2919, SEQ ID 2920, SEQ ID 2921, SEQ ID 2922, SEQ ID 2923, SEQ ID 2924, SEQ ID 2925, SEQ ID 2926, SEQ ID 2927, SEQ ID 2928, SEQ ID 2929, SEQ ID 2930, SEQ ID 2931, SEQ ID 2932, SEQ ID 2934, SEQ ID 2935, SEQ ID 2936, SEQ ID 2937, SEQ ID 2938, SEQ ID 2939, SEQ ID 2940, SEQ ID 2941, SEQ ID 2942, SEQ ID 2943, SEQ ID 2944, SEQ ID 2945, SEQ ID 2946, SEQ ID 2947, SEQ ID 2948, SEQ ID 2949, SEQ ID 2950, SEQ ID 2951, SEQ ID 2953, SEQ ID 2954, SEQ ID 2955, SEQ ID 2956, SEQ ID 2957, SEQ ID 2958, SEQ ID 2960, SEQ ID 2961, SEQ ID 2963, SEQ ID 2964, SEQ ID 2965, SEQ ID 2966, SEQ ID 2967, SEQ ID 2969, SEQ ID 2970, SEQ ID 2971, SEQ ID 2972, SEQ ID 2973, SEQ ID 2974, SEQ ID 2975, SEQ ID 2976, SEQ ID 2977, SEQ ID 2978, SEQ ID 2979, SEQ ID 2980, SEQ ID 2981, SEQ ID 2982, SEQ ID 2983, SEQ ID 2984, SEQ ID 2985, SEQ ID 3053, SEQ ID 3054, SEQ ID 3055, SEQ ID 3056, SEQ ID 3057, SEQ ID 3058, SEQ ID 3059, SEQ ID 3060, SEQ ID 3061, SEQ ID 3062, SEQ ID 3063, SEQ ID 3064, SEQ ID 3065, SEQ ID 3066, SEQ ID 3068, SEQ ID 3069, SEQ ID 3070, SEQ ID 3071, SEQ ID 3072, SEQ ID 3073, SEQ ID 3074, SEQ ID 3075, SEQ ID 3076, SEQ ID 3077, SEQ ID 3078, SEQ ID 3079, SEQ ID 3080, SEQ ID 3081, SEQ ID 3082, SEQ ID 3083, SEQ ID 3084, SEQ ID 3085, SEQ ID 3086, SEQ ID 3087, SEQ ID 3088, SEQ ID 3089, SEQ ID 3090, SEQ ID 3091, SEQ ID 3092, SEQ ID 3093, SEQ ID 3094, SEQ ID 3095, SEQ ID 3097, SEQ ID 3098, SEQ ID 3099, SEQ ID 3100, SEQ ID 3102, SEQ ID 3103, SEQ ID 3104, SEQ ID 3105, SEQ ID 3106, SEQ ID 3107, SEQ ID 3108, SEQ ID 3109, SEQ ID 3110, SEQ ID 3112, SEQ ID 3113, SEQ ID 3115, SEQ ID 3116, SEQ ID 3117, SEQ ID 3119, SEQ ID 3120, SEQ ID 3121, SEQ ID 3122, SEQ ID 3123, SEQ ID 3124, SEQ ID 3125, SEQ ID 3126, SEQ ID 3127, SEQ ID 3128, SEQ ID 3129, SEQ ID 3130, SEQ ID 3131, SEQ ID 3132, SEQ ID 3133, SEQ ID 3134, SEQ ID 3135, SEQ ID 3136, SEQ ID 3137, SEQ ID 3138, SEQ ID 3139, SEQ ID 3140, SEQ ID 3141, SEQ ID 3142, SEQ ID 3143, SEQ ID 3144, SEQ ID 3145, SEQ ID 3146, SEQ ID 3147, SEQ ID 3148, SEQ ID 3149, SEQ ID 3150, SEQ ID 3151, SEQ ID 3152, SEQ ID 3153, SEQ ID 3154, SEQ ID 3155, SEQ ID 3156, SEQ ID 3157, SEQ ID 3158, SEQ ID 3159, SEQ ID 3160, SEQ ID 3161, SEQ ID 3162, SEQ ID 3163, SEQ ID 3164, SEQ ID 3165, SEQ ID 3166, SEQ ID 3167, SEQ ID 3168, SEQ ID 3169, SEQ ID 3170, SEQ ID 3171, SEQ ID 3172, SEQ ID 3173, SEQ ID 3174, SEQ ID 3175, SEQ ID 3176, SEQ ID 3177, SEQ ID 3178, SEQ ID 3179, SEQ ID 3180, SEQ ID 3181, SEQ ID 3182, SEQ ID 3183, SEQ ID 3184, SEQ ID 3185, SEQ ID 3186, SEQ ID 3187, SEQ ID 3188, SEQ ID 3189, SEQ ID 3190, SEQ ID 3191, SEQ ID 3192, SEQ ID 3193, SEQ ID 3194, SEQ ID 3195, SEQ ID 3196, SEQ ID 3197, SEQ ID 3198, SEQ ID 3199, SEQ ID 3200, SEQ ID 3201, SEQ ID 3202, SEQ ID 3203, SEQ ID 3204, SEQ ID 3205, SEQ ID 3206, SEQ ID 3207, SEQ ID 3208, SEQ ID 3209, SEQ ID 3210, SEQ ID 3211, SEQ ID 3212, SEQ ID 3213, SEQ ID 3214, SEQ ID 3215, SEQ ID 3216, SEQ ID 3217, SEQ ID 3218, SEQ ID 3219, SEQ ID 3220, SEQ ID 3221, SEQ ID 3222, SEQ ID 3223, SEQ ID 3224, SEQ ID 3225, SEQ ID 3226, SEQ ID 3227, SEQ ID 3228, SEQ ID 3229, SEQ ID 3230, SEQ ID 3231, SEQ ID 3232, SEQ ID 3233, SEQ ID 3234, SEQ ID 3235, SEQ ID 3236, SEQ ID 3237, SEQ ID 3238, SEQ ID 3239, SEQ ID 3240, SEQ ID 3241, SEQ ID 3242, SEQ ID 3243, SEQ ID 3244, SEQ ID 3245, SEQ ID 3246, SEQ ID 3248, SEQ ID 3249, SEQ ID 3250, SEQ ID 3251, SEQ ID 3252, SEQ ID 3253, SEQ ID 3254, SEQ ID 3255, SEQ ID 3256, SEQ ID 3257, SEQ ID 3258, SEQ ID 3259, SEQ ID 3260, SEQ ID 3261, SEQ ID 3262, SEQ ID 3263, SEQ ID 3264, SEQ ID 3265, SEQ ID 3266, SEQ ID 3267, SEQ ID 3268, SEQ ID 3269, SEQ ID 3270, SEQ ID 3271, SEQ ID 3272, SEQ ID 3273, SEQ ID 3275, SEQ ID 3276, SEQ ID 3277, SEQ ID 3278, SEQ ID 3279, SEQ ID 3280, SEQ ID 3282, SEQ ID 3284, SEQ ID 3285, SEQ ID 3286, SEQ ID 3287, SEQ ID 3288, SEQ ID 3289, SEQ ID 3291, SEQ ID 3292, SEQ ID 3293, SEQ ID 3294, SEQ ID 3295, SEQ ID 3296, SEQ ID 3297, SEQ ID 3298, SEQ ID 3299, SEQ ID 3300, SEQ ID 3301, SEQ ID 3302, SEQ ID 3303, SEQ ID 3304, SEQ ID 3305, SEQ ID 3306, SEQ ID 3307, SEQ ID 3308, SEQ ID 3309, SEQ ID 3310, SEQ ID 3311, SEQ ID 3312, SEQ ID 3313, SEQ ID 3314, SEQ ID 3315, SEQ ID 3316, SEQ ID 3317, SEQ ID 3318, SEQ ID 3320, SEQ ID 3321, SEQ ID 3322, SEQ ID 3323, SEQ ID 3324, SEQ ID 3325, SEQ ID 3326, SEQ ID 3327, SEQ ID 3329, SEQ ID 3331, SEQ ID 3332, SEQ ID 3333, SEQ ID 3334, SEQ ID 3335, SEQ ID 3336, SEQ ID 3337, SEQ ID 3338, SEQ ID 3339, SEQ ID 3340, SEQ ID 3342, SEQ ID 3343, SEQ ID 3344, SEQ ID 3345, SEQ ID 3346, SEQ ID 3347, SEQ ID 3348, SEQ ID 3349, SEQ ID 3350, SEQ ID 3351, SEQ ID 3352, SEQ ID 3353, SEQ ID 3354, SEQ ID 3355, SEQ ID 3356, SEQ ID 3357, SEQ ID 3358, SEQ ID 3359, SEQ ID 3360, SEQ ID 3361, SEQ ID 3362, SEQ ID 3363, SEQ ID 3364, SEQ ID 3365, SEQ ID 3366, SEQ ID 3367, SEQ ID 3368, SEQ ID 3369, SEQ ID 3370, SEQ ID 3371, SEQ ID 3390, SEQ ID 3391, SEQ ID 3392, SEQ ID 3393, SEQ ID 3394, SEQ ID 3395, SEQ ID 3396, SEQ ID 3397, SEQ ID 3398, SEQ ID 3399, SEQ ID 3400, SEQ ID 3401, SEQ ID 3402, SEQ ID 3403, SEQ ID 3404, SEQ ID 3405, SEQ ID 3406, SEQ ID 3407, SEQ ID 3408, SEQ ID 3409, SEQ ID 3410, SEQ ID 3411, SEQ ID 3412, SEQ ID 3413, SEQ ID 3414, SEQ ID 3415, SEQ ID 3416, SEQ ID 3417, SEQ ID 3418, SEQ ID 3419, SEQ ID 3420, SEQ ID 3421, SEQ ID 3422, SEQ ID 3423, SEQ ID 3424, SEQ ID 3425, SEQ ID 3426, SEQ ID 3427, SEQ ID 3428, SEQ ID 3429, SEQ ID 3430, SEQ ID 3431, SEQ ID 3432, SEQ ID 3433, SEQ ID 3434, SEQ ID 3435, SEQ ID 3436, SEQ ID 3437, SEQ ID 3438, SEQ ID 3439, SEQ ID 3440, SEQ ID 3441, SEQ ID 3442, SEQ ID 3443, SEQ ID 3444, SEQ ID 3445, SEQ ID 3446, SEQ ID 3447, SEQ ID 3448, SEQ ID 3449, SEQ ID 3450, SEQ ID 3451, SEQ ID 3452, SEQ ID 3453, SEQ ID 3454, SEQ ID 3460, SEQ ID 3461, SEQ ID 3464, SEQ ID 3465, SEQ ID 3466, SEQ ID 3467, SEQ ID 3468, SEQ ID 3486, SEQ ID 3487, SEQ ID 3488, SEQ ID 3489, SEQ ID 3490, SEQ ID 3491, SEQ ID 3493, SEQ ID 3494, SEQ ID 3496, SEQ ID 3497, SEQ ID 3501, SEQ ID 3505, SEQ ID 3508, SEQ ID 3511, SEQ ID 3512, SEQ ID 3516, SEQ ID 3517, SEQ ID 3518, SEQ ID 3521, SEQ ID 3522, SEQ ID 3523, SEQ ID 3524, SEQ ID 3525, SEQ ID 3526, SEQ ID 3527, SEQ ID 3528, SEQ ID 3530, SEQ ID 3531, SEQ ID 3532, SEQ ID 3534, SEQ ID 3535, SEQ ID 3536, SEQ ID 3538, SEQ ID 3539, SEQ ID 3541, SEQ ID 3542, SEQ ID 3543, SEQ ID 3544, SEQ ID 3546, SEQ ID 3548, SEQ ID 3549, SEQ ID 3550, SEQ ID 3552, SEQ ID 3556, SEQ ID 3557, SEQ ID 3558, SEQ ID 3560, SEQ ID 3561, SEQ ID 3566, SEQ ID 3567, SEQ ID 3568, SEQ ID 3569, SEQ ID 3571, SEQ ID 3572, SEQ ID 3573, SEQ ID 3574, SEQ ID 3576, SEQ ID 3577, SEQ ID 3578, SEQ ID 3580, SEQ ID 3581, SEQ ID 3584, SEQ ID 3585, SEQ ID 3586, SEQ ID 3588, SEQ ID 3590, SEQ ID 3592, SEQ ID 3594, SEQ ID 3595, SEQ ID 3598, SEQ ID 3599, SEQ ID 3600, SEQ ID 3601, SEQ ID 3602, SEQ ID 3603, SEQ ID 3605, SEQ ID 3607, SEQ ID 3609, SEQ ID 3610, SEQ ID 3613, SEQ ID 3614, SEQ ID 3615, SEQ ID 3616, SEQ ID 3617, SEQ ID 3621, SEQ ID 3623, SEQ ID 3624, SEQ ID 3625, SEQ ID 3626, SEQ ID 3627, SEQ ID 3628, SEQ ID 3629, SEQ ID 3630, SEQ ID 3631, SEQ ID 3632, SEQ ID 3633, SEQ ID 3636, SEQ ID 3637, SEQ ID 3638, SEQ ID 3639, SEQ ID 3641, SEQ ID 3642, SEQ ID 3643, SEQ ID 3645, SEQ ID 3647, SEQ ID 3648, SEQ ID 3649, SEQ ID 3651, SEQ ID 3654, SEQ ID 3656, SEQ ID 3659, SEQ ID 3660, SEQ ID 3661, SEQ ID 3663, SEQ ID 3664, SEQ ID 3665, SEQ ID 3666, SEQ ID 3670, SEQ ID 3672, SEQ ID 3676, SEQ ID 3678, SEQ ID 3679, SEQ ID 3680, SEQ ID 3681, SEQ ID 3682, SEQ ID 3683, SEQ ID 3684, SEQ ID 3685, SEQ ID 3686, SEQ ID 3687, SEQ ID 3688, SEQ ID 3689, SEQ ID 3690, SEQ ID 3691, SEQ ID 3692, SEQ ID 3693, SEQ ID 3694, SEQ ID 3695, SEQ ID 3696, SEQ ID 3697, SEQ ID 3698, SEQ ID 3699, SEQ ID 3700, SEQ ID 3701, SEQ ID 3702, SEQ ID 3703, SEQ ID 3704, SEQ ID 3705, SEQ ID 3706, SEQ ID 3707, SEQ ID 3708, SEQ ID 3709, SEQ ID 3710, SEQ ID 3711, SEQ ID 3712, SEQ ID 3713, SEQ ID 3714, SEQ ID 3715, SEQ ID 3716, SEQ ID 3717, SEQ ID 3718, SEQ ID 3719, SEQ ID 3720, SEQ ID 3721, SEQ ID 3722, SEQ ID 3723, SEQ ID 3724, SEQ ID 3725, SEQ ID 3726, SEQ ID 3727, SEQ ID 3729, SEQ ID 3730, SEQ ID 3731, SEQ ID 3732, SEQ ID 3733, SEQ ID 3734, SEQ ID 3735, SEQ ID 3736, SEQ ID 3737, SEQ ID 3738, SEQ ID 3739, SEQ ID 3740, SEQ ID 3741, SEQ ID 3742, SEQ ID 3743, SEQ ID 3744, SEQ ID 3745, SEQ ID 3746, SEQ ID 3747, SEQ ID 3748, SEQ ID 3749, SEQ ID 3750, SEQ ID 3751, SEQ ID 3752, SEQ ID 3753, SEQ ID 3754, SEQ ID 3755, SEQ ID 3774, SEQ ID 3775, SEQ ID 3776, SEQ ID 3777, SEQ ID 3778, SEQ ID 3779, SEQ ID 3780, SEQ ID 3781, SEQ ID 3782, SEQ ID 3783, SEQ ID 3784, SEQ ID 3785, SEQ ID 3786, SEQ ID 3787, SEQ ID 3788, SEQ ID 3789, SEQ ID 3790, SEQ ID 3791, SEQ ID 3792, SEQ ID 3793, SEQ ID 3794, SEQ ID 3795, SEQ ID 3796, SEQ ID 3797, SEQ ID 3798, SEQ ID 3799, SEQ ID 3800, SEQ ID 3801, SEQ ID 3802, SEQ ID 3803, SEQ ID 3804, SEQ ID 3805, SEQ ID 3806, SEQ ID 3807, SEQ ID 3808, SEQ ID 3809, SEQ ID 3810, SEQ ID 3811, SEQ ID 3812, SEQ ID 3813, SEQ ID 3814, SEQ ID 3815, SEQ ID 3816, SEQ ID 3817, SEQ ID 3818, SEQ ID 3819, SEQ ID 3820, SEQ ID 3821, SEQ ID 3822, SEQ ID 3823, SEQ ID 3824, SEQ ID 3825, SEQ ID 3826, SEQ ID 3827, SEQ ID 3828, SEQ ID 3829, SEQ ID 3830, SEQ ID 3831, SEQ ID 3832, SEQ ID 3833, SEQ ID 3834, SEQ ID 3835, SEQ ID 3836, SEQ ID 3837, SEQ ID 3838, SEQ ID 3839, SEQ ID 3840, SEQ ID 3841, SEQ ID 3842, SEQ ID 3844, SEQ ID 3848, SEQ ID 3850, SEQ ID 3851, SEQ ID 3852, SEQ ID 3853, SEQ ID 3867, SEQ ID 3868, SEQ ID 3869, SEQ ID 3870, SEQ ID 3871, SEQ ID 3872, SEQ ID 3873, SEQ ID 3874, SEQ ID 3875, SEQ ID 3876, SEQ ID 3877, SEQ ID 3878, SEQ ID 3879, SEQ ID 3880, SEQ ID 3881, SEQ ID 3882, SEQ ID 3883, SEQ ID 3884, SEQ ID 3885, SEQ ID 3886, SEQ ID 3887, SEQ ID 3888, SEQ ID 3889, SEQ ID 3890, SEQ ID 3891, SEQ ID 3892, SEQ ID 3893, SEQ ID 3894, SEQ ID 3895, SEQ ID 3896, SEQ ID 3897, SEQ ID 3898, SEQ ID 3899, SEQ ID 3900, SEQ ID 3901, SEQ ID 3902, SEQ ID 3903, SEQ ID 3904, SEQ ID 3905, SEQ ID 3906, SEQ ID 3907, SEQ ID 3908, SEQ ID 3909, SEQ ID 3910, SEQ ID 3911, SEQ ID 3912, SEQ ID 3913, SEQ ID 3914, SEQ ID 3915, SEQ ID 3916, SEQ ID 3917, SEQ ID 3918, SEQ ID 3919, SEQ ID 3920, SEQ ID 3921, SEQ ID 3922, SEQ ID 3923, SEQ ID 3924, SEQ ID 3925, SEQ ID 3926, SEQ ID 3927, SEQ ID 3928, SEQ ID 3929, SEQ ID 3930, SEQ ID 3931, SEQ ID 3932, SEQ ID 3933, SEQ ID 3934, SEQ ID 3935, SEQ ID 3936, SEQ ID 3937, SEQ ID 3938, SEQ ID 3939, SEQ ID 3940, SEQ ID 3941, SEQ ID 3942, SEQ ID 3943, SEQ ID 3944, SEQ ID 3945, SEQ ID 3946, SEQ ID 3947, and SEQ ID 3948.

In some embodiments the target sequence is selected from the group consisting of SEQ ID 2321, SEQ ID 2335, SEQ ID 2336, SEQ ID 2337, SEQ ID 2338, SEQ ID 2339, SEQ ID 2348, SEQ ID 2349, SEQ ID 2351, SEQ ID 2352, SEQ ID 2353, SEQ ID 2354, SEQ ID 2355, SEQ ID 2358, SEQ ID 2360, SEQ ID 2364, SEQ ID 2365, SEQ ID 2366, SEQ ID 2367, SEQ ID 2369, SEQ ID 2371, SEQ ID 2373, SEQ ID 2375, SEQ ID 2386, SEQ ID 2387, SEQ ID 2388, SEQ ID 2389, SEQ ID 2394, SEQ ID 2403, SEQ ID 2426, SEQ ID 2428, SEQ ID 2429, SEQ ID 2430, SEQ ID 2431, SEQ ID 2432, SEQ ID 2435, SEQ ID 2440, SEQ ID 2441, SEQ ID 2442, SEQ ID 2444, SEQ ID 2446, SEQ ID 2447, SEQ ID 2450, SEQ ID 2451, SEQ ID 2452, SEQ ID 2453, SEQ ID 2454, SEQ ID 2455, SEQ ID 2456, SEQ ID 2458, SEQ ID 2459, SEQ ID 2461, SEQ ID 2463, SEQ ID 2464, SEQ ID 2465, SEQ ID 2466, SEQ ID 2467, SEQ ID 2468, SEQ ID 2469, SEQ ID 2470, SEQ ID 2471, SEQ ID 2472, SEQ ID 2473, SEQ ID 2474, SEQ ID 2475, SEQ ID 2476, SEQ ID 2477, SEQ ID 2478, SEQ ID 2482, SEQ ID 2483, SEQ ID 2484, SEQ ID 2485, SEQ ID 2487, SEQ ID 2489, SEQ ID 2494, SEQ ID 2495, SEQ ID 2496, SEQ ID 2497, SEQ ID 2499, SEQ ID 2501, SEQ ID 2502, SEQ ID 2504, SEQ ID 2506, SEQ ID 2507, SEQ ID 2508, SEQ ID 2509, SEQ ID 2511, SEQ ID 2513, SEQ ID 2515, SEQ ID 2516, SEQ ID 2518, SEQ ID 2519, SEQ ID 2520, SEQ ID 2521, SEQ ID 2523, SEQ ID 2525, SEQ ID 2534, SEQ ID 2537, SEQ ID 2544, SEQ ID 2546, SEQ ID 2554, SEQ ID 2555, SEQ ID 2556, SEQ ID 2560, SEQ ID 2561, SEQ ID 2562, SEQ ID 2595, SEQ ID 2626, SEQ ID 2628, SEQ ID 2629, SEQ ID 2630, SEQ ID 2631, SEQ ID 2633, SEQ ID 2638, SEQ ID 2639, SEQ ID 2640, SEQ ID 2649, SEQ ID 2651, SEQ ID 2652, SEQ ID 2655, SEQ ID 2658, SEQ ID 2665, SEQ ID 2666, SEQ ID 2667, SEQ ID 2669, SEQ ID 2670, SEQ ID 2676, SEQ ID 2677, SEQ ID 2678, SEQ ID 2679, SEQ ID 2682, SEQ ID 2686, SEQ ID 2688, SEQ ID 2689, SEQ ID 2691, SEQ ID 2694, SEQ ID 2698, SEQ ID 2699, SEQ ID 2700, SEQ ID 2701, SEQ ID 2703, SEQ ID 2706, SEQ ID 2709, SEQ ID 2711, SEQ ID 2712, SEQ ID 2713, SEQ ID 2714, SEQ ID 2719, SEQ ID 2720, SEQ ID 2721, SEQ ID 2737, SEQ ID 2739, SEQ ID 2740, SEQ ID 2741, SEQ ID 2742, SEQ ID 2743, SEQ ID 2744, SEQ ID 2745, SEQ ID 2746, SEQ ID 2747, SEQ ID 2748, SEQ ID 2749, SEQ ID 2750, SEQ ID 2751, SEQ ID 2752, SEQ ID 2753, SEQ ID 2754, SEQ ID 2755, SEQ ID 2756, SEQ ID 2757, SEQ ID 2758, SEQ ID 2760, SEQ ID 2763, SEQ ID 2764, SEQ ID 2765, SEQ ID 2766, SEQ ID 2767, SEQ ID 2768, SEQ ID 2769, SEQ ID 2770, SEQ ID 2771, SEQ ID 2772, SEQ ID 2774, SEQ ID 2816, SEQ ID 2817, SEQ ID 2818, SEQ ID 2819, SEQ ID 2820, SEQ ID 2824, SEQ ID 2828, SEQ ID 2829, SEQ ID 2830, SEQ ID 2831, SEQ ID 2832, SEQ ID 2833, SEQ ID 2834, SEQ ID 2835, SEQ ID 2836, SEQ ID 2837, SEQ ID 2851, SEQ ID 2852, SEQ ID 2866, SEQ ID 2871, SEQ ID 2872, SEQ ID 2886, SEQ ID 2887, SEQ ID 2890, SEQ ID 2891, SEQ ID 2892, SEQ ID 2895, SEQ ID 2896, SEQ ID 2899, SEQ ID 2904, SEQ ID 2910, SEQ ID 2911, SEQ ID 2912, SEQ ID 2913, SEQ ID 2914, SEQ ID 2916, SEQ ID 2918, SEQ ID 2919, SEQ ID 2920, SEQ ID 2922, SEQ ID 2925, SEQ ID 2926, SEQ ID 2932, SEQ ID 2939, SEQ ID 2941, SEQ ID 2942, SEQ ID 2943, SEQ ID 2972, SEQ ID 2973, SEQ ID 2974, SEQ ID 2975, SEQ ID 2976, SEQ ID 2977, SEQ ID 2980, SEQ ID 2983, SEQ ID 2985, SEQ ID 3053, SEQ ID 3054, SEQ ID 3055, SEQ ID 3056, SEQ ID 3058, SEQ ID 3059, SEQ ID 3060, SEQ ID 3061, SEQ ID 3062, SEQ ID 3063, SEQ ID 3064, SEQ ID 3065, SEQ ID 3066, SEQ ID 3068, SEQ ID 3069, SEQ ID 3070, SEQ ID 3071, SEQ ID 3072, SEQ ID 3073, SEQ ID 3074, SEQ ID 3075, SEQ ID 3076, SEQ ID 3077, SEQ ID 3078, SEQ ID 3079, SEQ ID 3082, SEQ ID 3083, SEQ ID 3084, SEQ ID 3085, SEQ ID 3088, SEQ ID 3089, SEQ ID 3090, SEQ ID 3091, SEQ ID 3092, SEQ ID 3095, SEQ ID 3097, SEQ ID 3102, SEQ ID 3106, SEQ ID 3108, SEQ ID 3110, SEQ ID 3116, SEQ ID 3120, SEQ ID 3121, SEQ ID 3125, SEQ ID 3126, SEQ ID 3133, SEQ ID 3134, SEQ ID 3135, SEQ ID 3137, SEQ ID 3138, SEQ ID 3140, SEQ ID 3141, SEQ ID 3142, SEQ ID 3143, SEQ ID 3145, SEQ ID 3148, SEQ ID 3152, SEQ ID 3153, SEQ ID 3156, SEQ ID 3157, SEQ ID 3158, SEQ ID 3159, SEQ ID 3160, SEQ ID 3161, SEQ ID 3162, SEQ ID 3163, SEQ ID 3164, SEQ ID 3165, SEQ ID 3166, SEQ ID 3167, SEQ ID 3168, SEQ ID 3169, SEQ ID 3170, SEQ ID 3172, SEQ ID 3173, SEQ ID 3174, SEQ ID 3175, SEQ ID 3176, SEQ ID 3177, SEQ ID 3178, SEQ ID 3179, SEQ ID 3180, SEQ ID 3181, SEQ ID 3182, SEQ ID 3183, SEQ ID 3184, SEQ ID 3186, SEQ ID 3188, SEQ ID 3191, SEQ ID 3193, SEQ ID 3196, SEQ ID 3197, SEQ ID 3203, SEQ ID 3205, SEQ ID 3206, SEQ ID 3207, SEQ ID 3210, SEQ ID 3211, SEQ ID 3212, SEQ ID 3213, SEQ ID 3214, SEQ ID 3215, SEQ ID 3216, SEQ ID 3217, SEQ ID 3218, SEQ ID 3219, SEQ ID 3221, SEQ ID 3222, SEQ ID 3223, SEQ ID 3224, SEQ ID 3227, SEQ ID 3236, SEQ ID 3237, SEQ ID 3238, SEQ ID 3239, SEQ ID 3240, SEQ ID 3241, SEQ ID 3242, SEQ ID 3243, SEQ ID 3244, SEQ ID 3245, SEQ ID 3246, SEQ ID 3248, SEQ ID 3249, SEQ ID 3250, SEQ ID 3251, SEQ ID 3252, SEQ ID 3254, SEQ ID 3258, SEQ ID 3259, SEQ ID 3261, SEQ ID 3263, SEQ ID 3265, SEQ ID 3266, SEQ ID 3267, SEQ ID 3271, SEQ ID 3272, SEQ ID 3273, SEQ ID 3276, SEQ ID 3277, SEQ ID 3279, SEQ ID 3286, SEQ ID 3295, SEQ ID 3297, SEQ ID 3305, SEQ ID 3307, SEQ ID 3309, SEQ ID 3312, SEQ ID 3313, SEQ ID 3314, SEQ ID 3316, SEQ ID 3317, SEQ ID 3318, SEQ ID 3320, SEQ ID 3332, SEQ ID 3335, SEQ ID 3336, SEQ ID 3337, SEQ ID 3338, SEQ ID 3339, SEQ ID 3340, SEQ ID 3342, SEQ ID 3343, SEQ ID 3345, SEQ ID 3346, SEQ ID 3347, SEQ ID 3348, SEQ ID 3349, SEQ ID 3350, SEQ ID 3351, SEQ ID 3352, SEQ ID 3353, SEQ ID 3354, SEQ ID 3355, SEQ ID 3356, SEQ ID 3359, SEQ ID 3360, SEQ ID 3361, SEQ ID 3362, SEQ ID 3363, SEQ ID 3364, SEQ ID 3365, SEQ ID 3366, SEQ ID 3369, SEQ ID 3370, SEQ ID 3390, SEQ ID 3392, SEQ ID 3393, SEQ ID 3394, SEQ ID 3395, SEQ ID 3396, SEQ ID 3397, SEQ ID 3398, SEQ ID 3399, SEQ ID 3401, SEQ ID 3403, SEQ ID 3404, SEQ ID 3407, SEQ ID 3408, SEQ ID 3409, SEQ ID 3410, SEQ ID 3411, SEQ ID 3412, SEQ ID 3413, SEQ ID 3414, SEQ ID 3415, SEQ ID 3417, SEQ ID 3419, SEQ ID 3420, SEQ ID 3422, SEQ ID 3423, SEQ ID 3424, SEQ ID 3428, SEQ ID 3429, SEQ ID 3430, SEQ ID 3432, SEQ ID 3433, SEQ ID 3434, SEQ ID 3435, SEQ ID 3436, SEQ ID 3437, SEQ ID 3439, SEQ ID 3440, SEQ ID 3441, SEQ ID 3442, SEQ ID 3443, SEQ ID 3444, SEQ ID 3445, SEQ ID 3446, SEQ ID 3447, SEQ ID 3448, SEQ ID 3449, SEQ ID 3450, SEQ ID 3451, SEQ ID 3452, SEQ ID 3460, SEQ ID 3461, SEQ ID 3466, SEQ ID 3467, SEQ ID 3468, SEQ ID 3490, SEQ ID 3494, SEQ ID 3496, SEQ ID 3501, SEQ ID 3505, SEQ ID 3511, SEQ ID 3512, SEQ ID 3516, SEQ ID 3517, SEQ ID 3521, SEQ ID 3522, SEQ ID 3556, SEQ ID 3557, SEQ ID 3561, SEQ ID 3566, SEQ ID 3567, SEQ ID 3568, SEQ ID 3569, SEQ ID 3571, SEQ ID 3572, SEQ ID 3576, SEQ ID 3578, SEQ ID 3580, SEQ ID 3584, SEQ ID 3594, SEQ ID 3613, SEQ ID 3614, SEQ ID 3624, SEQ ID 3625, SEQ ID 3626, SEQ ID 3627, SEQ ID 3628, SEQ ID 3633, SEQ ID 3641, SEQ ID 3643, SEQ ID 3648, SEQ ID 3651, SEQ ID 3654, SEQ ID 3656, SEQ ID 3659, SEQ ID 3660, SEQ ID 3661, SEQ ID 3670, SEQ ID 3676, SEQ ID 3680, SEQ ID 3681, SEQ ID 3683, SEQ ID 3684, SEQ ID 3685, SEQ ID 3686, SEQ ID 3687, SEQ ID 3688, SEQ ID 3689, SEQ ID 3691, SEQ ID 3693, SEQ ID 3694, SEQ ID 3695, SEQ ID 3696, SEQ ID 3698, SEQ ID 3700, SEQ ID 3701, SEQ ID 3703, SEQ ID 3704, SEQ ID 3707, SEQ ID 3708, SEQ ID 3709, SEQ ID 3710, SEQ ID 3711, SEQ ID 3712, SEQ ID 3713, SEQ ID 3714, SEQ ID 3715, SEQ ID 3716, SEQ ID 3717, SEQ ID 3718, SEQ ID 3719, SEQ ID 3720, SEQ ID 3721, SEQ ID 3722, SEQ ID 3723, SEQ ID 3725, SEQ ID 3744, SEQ ID 3747, SEQ ID 3748, SEQ ID 3749, SEQ ID 3750, SEQ ID 3751, SEQ ID 3752, SEQ ID 3753, SEQ ID 3754, SEQ ID 3755, SEQ ID 3774, SEQ ID 3775, SEQ ID 3776, SEQ ID 3786, SEQ ID 3788, SEQ ID 3790, SEQ ID 3791, SEQ ID 3793, SEQ ID 3794, SEQ ID 3795, SEQ ID 3796, SEQ ID 3797, SEQ ID 3798, SEQ ID 3799, SEQ ID 3800, SEQ ID 3801, SEQ ID 3802, SEQ ID 3803, SEQ ID 3804, SEQ ID 3805, SEQ ID 3809, SEQ ID 3810, SEQ ID 3811, SEQ ID 3812, SEQ ID 3813, SEQ ID 3814, SEQ ID 3815, SEQ ID 3821, SEQ ID 3822, SEQ ID 3823, SEQ ID 3824, SEQ ID 3825, SEQ ID 3826, SEQ ID 3827, SEQ ID 3828, SEQ ID 3830, SEQ ID 3831, SEQ ID 3832, SEQ ID 3834, SEQ ID 3836, SEQ ID 3837, SEQ ID 3838, SEQ ID 3839, SEQ ID 3840, SEQ ID 3841, SEQ ID 3842, SEQ ID 3844, SEQ ID 3850, SEQ ID 3852, SEQ ID 3867, SEQ ID 3868, SEQ ID 3870, SEQ ID 3871, SEQ ID 3872, SEQ ID 3873, SEQ ID 3874, SEQ ID 3875, SEQ ID 3876, SEQ ID 3879, SEQ ID 3880, SEQ ID 3881, SEQ ID 3882, SEQ ID 3883, SEQ ID 3884, SEQ ID 3885, SEQ ID 3886, SEQ ID 3887, SEQ ID 3888, SEQ ID 3889, SEQ ID 3890, SEQ ID 3891, SEQ ID 3892, SEQ ID 3893, SEQ ID 3894, SEQ ID 3895, SEQ ID 3896, SEQ ID 3897, SEQ ID 3908, SEQ ID 3909, SEQ ID 3910, SEQ ID 3911, SEQ ID 3912, SEQ ID 3913, SEQ ID 3922, SEQ ID 3923, SEQ ID 3930, SEQ ID 3935, SEQ ID 3936, SEQ ID 3937, SEQ ID 3938, SEQ ID 3939, SEQ ID 3940, SEQ ID 3944, SEQ ID 3945, SEQ ID 3946, SEQ ID 3947, and SEQ ID 3948.

In some embodiments the oligonucleotide comprises the contiguous nucleotide sequence, and may optionally comprise further nucleotide(s), for example a nucleotide linker region which may be used to attach a functional group (e.g. a conjugate group) to the contiguous nucleotide sequence. The nucleotide linker region may or may not be complementary to the target nucleic acid. It is understood that the contiguous nucleotide sequence of the oligonucleotide cannot be longer than the oligonucleotide as such and that the oligonucleotide cannot be shorter than the contiguous nucleotide sequence.

Nucleotides and Nucleosides

Nucleotides and nucleosides are the building blocks of oligonucleotides and polynucleotides, and for the purposes of the present invention include both naturally occurring and non-naturally occurring nucleotides and nucleosides. In nature, nucleotides, such as DNA and RNA nucleotides comprise a ribose sugar moiety, a nucleobase moiety and one or more phosphate groups (which is absent in nucleosides). Nucleosides and nucleotides may also interchangeably be referred to as “units” or “monomers”.

Modified Nucleoside

Advantageously, the antisense oligonucleotide progranulin agonist of the invention may comprise one or more modified nucleoside.

The term “modified nucleoside” or “nucleoside modification” as used herein refers to nucleosides modified as compared to the equivalent DNA or RNA nucleoside by the introduction of one or more modifications of the sugar moiety or the (nucleo)base moiety. Advantageously, one or more of the modified nucleosides of the antisense oligonucleotides of the invention may comprise a modified sugar moiety. The term modified nucleoside may also be used herein interchangeably with the term “nucleoside analogue” or modified “units” or modified “monomers”. Nucleosides with an unmodified DNA or RNA sugar moiety are termed DNA or RNA nucleosides herein. Nucleosides with modifications in the base region of the DNA or RNA nucleoside are still generally termed DNA or RNA if they allow Watson Crick base pairing. Exemplary modified nucleosides which may be used in the antisense oligonucleotide progranulin agonists of the invention include LNA, 2′-O-MOE, 2′oMe and morpholino nucleoside analogues.

Modified Internucleoside Linkage

Advantageously, the antisense oligonucleotide progranulin agonist of the invention comprises one or more modified internucleoside linkage.

The term “modified internucleoside linkage” is defined as generally understood by the skilled person as linkages other than phosphodiester (PO) linkages, that covalently couple two nucleosides together. The antisense oligonucleotide progranulin agonists of the invention may therefore comprise one or more modified internucleoside linkages such as one or more phosphorothioate internucleoside linkage.

In some embodiments at least 50% of the internucleoside linkages in the antisense oligonucleotide progranulin agonist, or contiguous nucleotide sequence thereof, are phosphorothioate, such as at least 60%, such as at least 70%, such as at least 75%, such as at least 80%, such as at least 90% or more of the internucleoside linkages in the antisense oligonucleotide progranulin agonist, or contiguous nucleotide sequence thereof, are phosphorothioate. In some embodiments all of the internucleoside linkages of the antisense oligonucleotide progranulin agonist, or contiguous nucleotide sequence thereof, are phosphorothioate.

Advantageously, all the internucleoside linkages of the contiguous nucleotide sequence of the antisense oligonucleotide progranulin agonist may be phosphorothioate, or all the internucleoside linkages of the antisense oligonucleotide progranulin agonist may be phosphorothioate linkages.

Nucleobase

The term nucleobase includes the purine (e.g. adenine and guanine) and pyrimidine (e.g. uracil, thymine and cytosine) moiety present in nucleosides and nucleotides which form hydrogen bonds in nucleic acid hybridization. In the context of the present invention the term nucleobase also encompasses modified nucleobases which may differ from naturally occurring nucleobases, but which are functional during nucleic acid hybridization. In this context “nucleobase” refers to both naturally occurring nucleobases such as adenine, guanine, cytosine, thymidine, uracil, xanthine and hypoxanthine, as well as non-naturally occurring variants. Such variants are for example described in Hirao et al (2012) Accounts of Chemical Research vol 45 page 2055 and Bergstrom (2009) Current Protocols in Nucleic Acid Chemistry Suppl. 37 1.4.1.

In some embodiments the nucleobase moiety is modified by changing the purine or pyrimidine into a modified purine or pyrimidine, such as substituted purine or substituted pyrimidine, such as a nucleobase selected from isocytosine, pseudoisocytosine, 5-methyl cytosine, 5-thiozolo-cytosine, 5-propynyl-cytosine, 5-propynyl-uracil, 5-bromouracil 5-thiazolo-uracil, 2-thio-uracil, 2′thio-thymine, inosine, diaminopurine, 6-aminopurine, 2-aminopurine, 2,6-diaminopurine and 2-chloro-6-aminopurine.

The nucleobase moieties may be indicated by the letter code for each corresponding nucleobase, e.g. A, T, G, C or U, wherein each letter may optionally include modified nucleobases of equivalent function. For example, in the exemplified oligonucleotides, the nucleobase moieties are selected from A, T, G, C, and 5-methyl cytosine. Optionally, for LNA gapmers, 5-methyl cytosine LNA nucleosides may be used.

Modified Oligonucleotide

The antisense oligonucleotide progranulin agonist of the invention may be a modified oligonucleotide.

The term modified oligonucleotide describes an oligonucleotide comprising one or more sugar-modified nucleosides and/or modified internucleoside linkages. The term “chimeric oligonucleotide” is a term that has been used in the literature to describe oligonucleotides comprising sugar modified nucleosides and DNA nucleosides. In some embodiments, it may be advantageous for the antisense oligonucleotide progranulin agonist of the invention to be a chimeric oligonucleotide.

Complementarity

The term “complementarity” describes the capacity for Watson-Crick base-pairing of nucleosides/nucleotides. Watson-Crick base pairs are guanine (G)-cytosine (C) and adenine (A)-thymine (T)/uracil (U).

It will be understood that oligonucleotides may comprise nucleosides with modified nucleobases, for example 5-methyl cytosine is often used in place of cytosine, and as such the term complementarity encompasses Watson Crick base-paring between non-modified and modified nucleobases (see for example Hirao et al (2012) Accounts of Chemical Research vol 45 page 2055 and Bergstrom (2009) Current Protocols in Nucleic Acid Chemistry Suppl. 37 1.4.1).

The term “% complementary” as used herein, refers to the proportion of nucleotides (in percent) of a contiguous nucleotide sequence in a nucleic acid molecule (e.g. oligonucleotide) which across the contiguous nucleotide sequence, are complementary to a reference sequence (e.g. a target sequence or sequence motif). The percentage of complementarity is thus calculated by counting the number of aligned nucleobases that are complementary (from Watson Crick base pairs) between the two sequences (when aligned with the target sequence 5′-3′ and the oligonucleotide sequence from 3′-5′), dividing that number by the total number of nucleotides in the oligonucleotide and multiplying by 100. In such a comparison a nucleobase/nucleotide which does not align (form a base pair) is termed a mismatch. Insertions and deletions are not allowed in the calculation of complementarity of a contiguous nucleotide sequence. It will be understood that in determining complementarity, chemical modifications of the nucleobases are disregarded as long as the functional capacity of the nucleobase to form Watson Crick base pairing is retained (e.g. 5′-methyl cytosine is considered identical to a cytosine for the purpose of calculating % identity).

Within the present invention the term “complementary” requires the antisense oligonucleotide progranulin agonist to be at least about 80% complementary, or at least about 90% complementary, to a human progranulin precursor-mRNA (pre-mRNA) or mature mRNA transcript. In some embodiments the antisense oligonucleotide progranulin agonist may be at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98% or at least about 99% complementary to a human progranulin precursor-mRNA (pre-mRNA) or mature mRNA transcript. Put another way, for some embodiments, an antisense oligonucleotide progranulin agonist of the invention may include one, two, three or more mis-matches, wherein a mis-match is a nucleotide within the antisense oligonucleotide progranulin agonist of the invention which does not base pair with its target.

The term “fully complementary”, refers to 100% complementarity.

The antisense oligonucleotide progranulin agonists of the invention are advantageously complementary to the human progranulin precursor mRNA (pre-mRNA) or the human prograulin mature mRNA sequence. The human progranulin mature mRNA sequence is exemplified herein as SEQ ID NO 1. The human progranulin precursor-mRNA (pre-mRNA) sequence is exemplified herein as SEQ ID NO 3949. SEQ ID NO 1 and SEQ ID NO 3949 are provided herein as reference sequences and it will be understood that the target progranulin nucleic acid may be an allelic variant of SEQ ID NO 1 or SEQ ID NO 3949, such as an allelic variant which comprises one or more polymorphism in the human progranulin nucleic acid sequence.

Identity

The term “identity” as used herein, refers to the proportion of nucleotides (expressed in percent) of a contiguous nucleotide sequence in a nucleic acid molecule (e.g. oligonucleotide) which across the contiguous nucleotide sequence, are identical to a reference sequence (e.g. a sequence motif).

The percentage of identity is thus calculated by counting the number of aligned nucleobases that are identical (a Match) between two sequences (in the contiguous nucleotide sequence of the compound of the invention and in the reference sequence), dividing that number by the total number of nucleotides in the oligonucleotide and multiplying by 100. Therefore, Percentage of Identity=(Matches×100)/Length of aligned region (e.g. the contiguous nucleotide sequence). Insertions and deletions are not allowed in the calculation the percentage of identity of a contiguous nucleotide sequence. It will be understood that in determining identity, chemical modifications of the nucleobases are disregarded as long as the functional capacity of the nucleobase to form Watson Crick base pairing is retained (e.g. 5-methyl cytosine is considered identical to a cytosine for the purpose of calculating % identity).

Hybridization

The terms “hybridizing” or “hybridizes” as used herein are to be understood as two nucleic acid strands (e.g. an oligonucleotide and a target nucleic acid) forming hydrogen bonds between base pairs on opposite strands thereby forming a duplex. The affinity of the binding between two nucleic acid strands is the strength of the hybridization. It is often described in terms of the melting temperature (T_m) defined as the temperature at which half of the oligonucleotides are duplexed with the target nucleic acid. At physiological conditions T_mis not strictly proportional to the affinity (Mergny and Lacroix, 2003, Oligonucleotides 13:515-537). The standard state Gibbs free energy ΔG° is a more accurate representation of binding affinity and is related to the dissociation constant (K_d) of the reaction by ΔG°=−RTln(K_d), where R is the gas constant and T is the absolute temperature. Therefore, a very low ΔG° of the reaction between an oligonucleotide and the target nucleic acid reflects a strong hybridization between the oligonucleotide and target nucleic acid. ΔG° is the energy associated with a reaction where aqueous concentrations are 1M, the pH is 7, and the temperature is 37° C. The hybridization of oligonucleotides to a target nucleic acid is a spontaneous reaction and for spontaneous reactions ΔG° is less than zero. ΔG° can be measured experimentally, for example, by use of the isothermal titration calorimetry (ITC) method as described in Hansen et al., 1965, Chem. Comm. 36-38 and Holdgate et al., 2005, Drug Discov Today. The skilled person will know that commercial equipment is available for ΔG° measurements. ΔG° can also be estimated numerically by using the nearest neighbor model as described by SantaLucia, 1998, Proc Natl Acad Sci USA. 95: 1460-1465 using appropriately derived thermodynamic parameters described by Sugimoto et al., 1995, Biochemistry 34:11211-11216 and McTigue et al., 2004, Biochemistry 43:5388-5405.

In some embodiments, antisense oligonucleotide progranulin agonists of the present invention hybridize to a target nucleic acid with estimated ΔG° values below −10 kcal for oligonucleotides that are 10-30 nucleotides in length.

In some embodiments the degree or strength of hybridization is measured by the standard state Gibbs free energy ΔG°. The oligonucleotides may hybridize to a target nucleic acid with estimated ΔG° values below the range of −10 kcal, such as below −15 kcal, such as below −20 kcal and such as below −25 kcal for oligonucleotides that are 8-30 nucleotides in length. In some embodiments the oligonucleotides hybridize to a target nucleic acid with an estimated ΔG° value of −10 to −60 kcal, such as −12 to −40, such as from −15 to −30 kcal, or −16 to −27 kcal such as −18 to −25 kcal.

High Affinity Modified Nucleosides

A high affinity modified nucleoside is a modified nucleotide which, when incorporated into the oligonucleotide enhances the affinity of the oligonucleotide for its complementary target, for example as measured by the melting temperature (T^m). A high affinity modified nucleoside of the present invention preferably results in an increase in melting temperature between +0.5 to +12° C., more preferably between +1.5 to +10° C. and most preferably between +3 to +8° C. per modified nucleoside. Numerous high affinity modified nucleosides are known in the art and include for example, many 2′ substituted nucleosides as well as locked nucleic acids (LNA) (see e.g. Freier & Altmann; Nucl. Acid Res., 1997, 25, 4429-4443 and Uhlmann; Curr. Opinion in Drug Development, 2000, 3(2), 293-213).

Sugar Modifications

The antisense oligonucleotide progranulin agonist of the invention may comprise one or more nucleosides which have a modified sugar moiety, i.e. a modification of the sugar moiety when compared to the ribose sugar moiety found in DNA and RNA.

Numerous nucleosides with modification of the ribose sugar moiety have been made, primarily with the aim of improving certain properties of oligonucleotides, such as affinity and/or nuclease resistance.

Such modifications include those where the ribose ring structure is modified, e.g. by replacement with a hexose ring (HNA), or a bicyclic ring, which typically have a biradicle bridge between the C2 and C4 carbons on the ribose ring (LNA), or an unlinked ribose ring which typically lacks a bond between the C2 and C3 carbons (e.g. UNA). Other sugar modified nucleosides include, for example, bicyclohexose nucleic acids (WO2011/017521) or tricyclic nucleic acids (WO2013/154798). Modified nucleosides also include nucleosides where the sugar moiety is replaced with a non-sugar moiety, for example in the case of peptide nucleic acids (PNA), or morpholino nucleic acids.

Sugar modifications also include modifications made via altering the substituent groups on the ribose ring to groups other than hydrogen, or the 2′-OH group naturally found in DNA and RNA nucleosides. Substituents may, for example be introduced at the 2′, 3′, 4′ or 5′ positions.

2′ Sugar Modified Nucleosides

A 2′ sugar modified nucleoside is a nucleoside which has a substituent other than H or —OH at the 2′ position (2′ substituted nucleoside) or comprises a 2′ linked biradicle capable of forming a bridge between the 2′ carbon and a second carbon in the ribose ring, such as LNA (2′-4′ biradicle bridged) nucleosides.

Indeed, much focus has been spent on developing 2′ sugar substituted nucleosides, and numerous 2′ substituted nucleosides have been found to have beneficial properties when incorporated into oligonucleotides. For example, the 2′ modified sugar may provide enhanced binding affinity and/or increased nuclease resistance to the oligonucleotide. Examples of 2′ substituted modified nucleosides are 2′-O-alkyl-RNA, 2′-O-methyl-RNA (2′oMe), 2′-alkoxy-RNA, 2′-O-methoxyethyl-RNA (MOE), 2′-amino-DNA, 2′-Fluoro-RNA, and 2′-F-ANA nucleoside. For further examples, please see e.g. Freier & Altmann; Nucl. Acid Res., 1997, 25, 4429-4443 and Uhlmann; Curr. Opinion in Drug Development, 2000, 3(2), 293-213, and Deleavey and Damha, Chemistry and Biology 2012, 19, 937. Below are illustrations of some 2′ substituted modified nucleosides.

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In relation to the present invention 2′ substituted sugar modified nucleosides does not include 2′ bridged nucleosides like LNA.

Locked Nucleic Acid Nucleosides (LNA Nucleoside)

A “LNA nucleoside” is a 2′-modified nucleoside which comprises a biradical linking the C2′ and C4′ of the ribose sugar ring of said nucleoside (also referred to as a “2′-4′ bridge”), which restricts or locks the conformation of the ribose ring. These nucleosides are also termed bridged nucleic acid or bicyclic nucleic acid (BNA) in the literature. The locking of the conformation of the ribose is associated with an enhanced affinity of hybridization (duplex stabilization) when the LNA is incorporated into an oligonucleotide for a complementary RNA or DNA molecule. This can be routinely determined by measuring the melting temperature of the oligonucleotide/complement duplex.

Non limiting, exemplary LNA nucleosides are disclosed in WO 99/014226, WO 00/66604, WO 98/039352, WO 2004/046160, WO 00/047599, WO 2007/134181, WO 2010/077578, WO 2010/036698, WO 2007/090071, WO 2009/006478, WO 2011/156202, WO 2008/154401, WO 2009/067647, WO 2008/150729, Morita et al., Bioorganic & Med. Chem. Lett. 12, 73-76, Seth et al. J. Org. Chem. 2010, Vol 75(5) pp. 1569-81, and Mitsuoka et al., Nucleic Acids Research 2009, 37(4), 1225-1238, and Wan and Seth, J. Medical Chemistry 2016, 59, 9645-9667.

Further non limiting, exemplary LNA nucleosides are disclosed in Scheme 1.

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Particular LNA nucleosides are beta-D-oxy-LNA, 6′-methyl-beta-D-oxy LNA such as (S)-6′-methyl-beta-D-oxy-LNA (ScET) and ENA.

A particularly advantageous LNA is beta-D-oxy-LNA.

Morpholino Oligonucleotides

In some embodiments, the antisense oligonucleotide progranulin agonist of the invention comprises or consists of morpholino nucleosides (i.e. is a Morpholino oligomer and as a phosphorodiamidate Morpholino oligomer (PMO)). Splice modulating morpholino oligonucleotides have been approved for clinical use—see for example eteplirsen, a 30nt morpholino oligonucleotide targeting a frame shift mutation in DMD, used to treat Duchenne muscular dystrophy. Morpholino oligonucleotides have nucleobases attached to six membered morpholine rings rather ribose, such as methylenemorpholine rings linked through phosphorodiamidate groups, for example as illustrated by the following illustration of 4 consecutive morpholino nucleotides:

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In some embodiments, morpholino oligonucleotides of the invention may be, for example 20-40 morpholino nucleotides in length, such as morpholino 25-35 nucleotides in length.

RNase H Activity and Recruitment

The RNase H activity of an antisense oligonucleotide refers to its ability to recruit RNase H when in a duplex with a complementary RNA molecule. WO01/23613 provides in vitro methods for determining RNaseH activity, which may be used to determine the ability to recruit RNaseH. Typically an oligonucleotide is deemed capable of recruiting RNase H if it, when provided with a complementary target nucleic acid sequence, has an initial rate, as measured in pmol/l/min, of at least 5%, such as at least 10%, at least 20% or more than 20%, of the initial rate determined when using an oligonucleotide having the same base sequence as the modified oligonucleotide being tested, but containing only DNA monomers with phosphorothioate linkages between all monomers in the oligonucleotide, and using the methodology provided by Examples 91-95 of WO01/23613 (hereby incorporated by reference). For use in determining RHase H activity, recombinant RNase H1 is available from Lubio Science GmbH, Lucerne, Switzerland.

DNA oligonucleotides are known to effectively recruit RNaseH, as are gapmer oligonucleotides which comprise a region of DNA nucleosides (typically at least 5 or 6 contiguous DNA nucleosides), flanked 5′ and 3′ by regions comprising 2′ sugar modified nucleosides, typically high affinity 2′ sugar modified nucleosides, such as 2-O-MOE and/or LNA. For effective modulation of splicing, degradation of the pre-mRNA is not desirable, and as such it is preferable to avoid the RNaseH degradation of the target. Therefore, the antisense oligonucleotide progranulin agonists of the invention are not RNaseH recruiting gapmer oligonucleotide.

RNaseH recruitment may be avoided by limiting the number of contiguous DNA nucleotides in the oligonucleotide—therefore mimxes and totalmer designs may be used. Advanateously the antisense oligonucleotide progranulin agonistd of the invention, or the contiguous nucleotide sequence thereof, do not comprise more than 3 contiguous DNA nucleosides. Further, advanateously the antisense oligonucleotide progranulin agonists of the invention, or the contiguous nucleotide sequence thereof, do not comprise more than 4 contiguous DNA nucleosides. Further advantageously, the progranulin agonist antisense oligonucleotide agonists of the invention, or contiguous nucleotide sequence thereof, do not comprise more than 2 contiguous DNA nucleosides.

Mixmers and Totalmers

For splice modulation it is often advantageous to use antisense oligonucleotides which do not recruit RNAaseH. As RNaseH activity requires a contiguous sequence of DNA nucleotides, RNaseH activity of antisense oligonucleotide may be achieved by designing antisense oligonucleotides which do not comprise a region of more than 3 or more than 4 contiguous DNA nucleosides. This may be achieved by using antisense oligonucleotides or contiguous nucleoside regions thereof with a mixmer design, which comprise sugar modified nucleosides, such as 2′ sugar modified nucleosides, and short regions of DNA nucleosides, such as 1, 2 or 3 DNA nucleosides. Mixmers are exemplified herein by every second design, wherein the nucleosides alternate between 1 LNA and 1 DNA nucleoside, e.g. LDLDLDLDLDLDLDLL, with 5′ and 3′ terminal LNA nucleosides, and every third design, such as LDDLDDLDDLDDLDDL, where every third nucleoside is a LNA nucleoside.

A totalmer is an antisense oligonucleotide or a contiguous nucleotide sequence thereof which does not comprise DNA or RNA nucleosides, and may for example comprise only 2′-O-MOE nucleosides, such as a fully MOE phosphorothioate, e.g. MMMMMMMMMMMMMMMMMMMM, where M=2′-O-MOE, or may for example comprise only 2′oMe nucleosides, which are reported to be effective splice modulators for therapeutic use.

Alternatively, a mixmer may comprise a mixture of modified nucleosides, such as MLMLMLMLMLMLMLMLMLML, wherein L=LNA and M=2′-O-MOE nucleosides. Advantageously, the internucleoside nucleosides in mixmers and totalmers may be phosphorothioate, or a majority of nucleoside linkages in mixmers may be phosphorothioate. Mixmers and totalmers may comprise other internucleoside linkages, such as phosphodiester or phosphorodithioate, by way of example.

Region D′ or D″ in an Oligonucleotide

The antisense oligonucleotide progranulin agonist of the invention may in some embodiments comprise or consist of the contiguous nucleotide sequence of the oligonucleotide which is complementary to the target nucleic acid, such as a mixmer or toalmer region, and further 5′ and/or 3′ nucleosides. The further 5′ and/or 3′ nucleosides may or may not be complementary, such as fully complementary, to the target nucleic acid. Such further 5′ and/or 3′ nucleosides may be referred to as region D′ and D″ herein.

The addition of region D′ or D″ may be used for the purpose of joining the contiguous nucleotide sequence, such as the mixmer or totoalmer, to a conjugate moiety or another functional group. When used for joining the contiguous nucleotide sequence with a conjugate moiety is can serve as a biocleavable linker. Alternatively, it may be used to provide exonucleoase protection or for ease of synthesis or manufacture.

Region D′ or D″ may independently comprise or consist of 1, 2, 3, 4 or 5 additional nucleotides, which may be complementary or non-complementary to the target nucleic acid. The nucleotide adjacent to the F or F′ region is not a sugar-modified nucleotide, such as a DNA or RNA or base modified versions of these. The D′ or D′ region may serve as a nuclease susceptible biocleavable linker (see definition of linkers). In some embodiments the additional 5′ and/or 3′ end nucleotides are linked with phosphodiester linkages, and are DNA or RNA. Nucleotide based biocleavable linkers suitable for use as region D′ or D″ are disclosed in WO2014/076195, which include by way of example a phosphodiester linked DNA dinucleotide. The use of biocleavable linkers in poly-oligonucleotide constructs is disclosed in WO2015/113922, where they are used to link multiple antisense constructs within a single oligonucleotide.

In one embodiment the antisense oligonucleotide progranulin agonist of the invention comprises a region D′ and/or D″ in addition to the contiguous nucleotide sequence which constitutes a mixmer or a totalmer.

In some embodiments the internucleoside linkage positioned between region D′ or D″ and the mixmer or totalmer region is a phosphodiester linkage.

Conjugate

The invention encompasses an antisense oligonucleotide progranulin agonist covalently attached to at least one conjugate moiety. In some embodiments this may be referred to as a conjugate of the invention.

The term “conjugate” as used herein refers to an antisense oligonucleotide progranulin agonist which is covalently linked to a non-nucleotide moiety (conjugate moiety or region C or third region). The conjugate moiety may be covalentaly linked to the antisense oligonucleotide, optionally via a linker group, such as region D′ or D″.

Oligonucleotide conjugates and their synthesis has also been reported in comprehensive reviews by Manoharan in Antisense Drug Technology, Principles, Strategies, and Applications, S. T. Crooke, ed., Ch. 16, Marcel Dekker, Inc., 2001 and Manoharan, Antisense and Nucleic Acid Drug Development, 2002, 12, 103.

In some embodiments, the non-nucleotide moiety (conjugate moiety) is selected from the group consisting of carbohydrates (e.g. GalNAc), cell surface receptor ligands, drug substances, hormones, lipophilic substances, polymers, proteins, peptides, toxins (e.g. bacterial toxins), vitamins, viral proteins (e.g. capsids) or combinations thereof.

Linkers

A linkage or linker is a connection between two atoms that links one chemical group or segment of interest to another chemical group or segment of interest via one or more covalent bonds. Conjugate moieties can be attached to the antisense oligonucleotide progranulin agonist directly or through a linking moiety (e.g. linker or tether). Linkers serve to covalently connect a third region, e.g. a conjugate moiety (Region C), to a first region, e.g. an oligonucleotide or contiguous nucleotide sequence complementary to the target nucleic acid (region A).

In some embodiments of the invention the conjugate or antisense oligonucleotide progranulin agonist conjugate of the invention may optionally comprise a linker region (second region or region B and/or region Y) which is positioned between the oligonucleotide or contiguous nucleotide sequence complementary to the target nucleic acid (region A or first region) and the conjugate moiety (region C or third region).

Region B refers to biocleavable linkers comprising or consisting of a physiologically labile bond that is cleavable under conditions normally encountered or analogous to those encountered within a mammalian body. Conditions under which physiologically labile linkers undergo chemical transformation (e.g., cleavage) include chemical conditions such as pH, temperature, oxidative or reductive conditions or agents, and salt concentration found in or analogous to those encountered in mammalian cells. Mammalian intracellular conditions also include the presence of enzymatic activity normally present in a mammalian cell such as from proteolytic enzymes or hydrolytic enzymes or nucleases. In one embodiment the biocleavable linker is susceptible to S1 nuclease cleavage. In some embodiments the nuclease susceptible linker comprises between 1 and 5 nucleosides, such as DNA nucleoside(s) comprising at least two consecutive phosphodiester linkages. Phosphodiester containing biocleavable linkers are described in more detail in WO 2014/076195.

Region Y refers to linkers that are not necessarily biocleavable but primarily serve to covalently connect a conjugate moiety (region C or third region), to an oligonucleotide (region A or first region). The region Y linkers may comprise a chain structure or an oligomer of repeating units such as ethylene glycol, amino acid units or amino alkyl groups The antisense oligonucleotide progranulin agonist conjugates of the present invention can be constructed of the following regional elements A-C, A-B-C, A-B-Y-C, A-Y-B-C or A-Y-C. In some embodiments the linker (region Y) is an amino alkyl, such as a C2-C36 amino alkyl group, including, for example C6 to C12 amino alkyl groups. In some embodiments the linker (region Y) is a C6 amino alkyl group.

Treatment

The term ‘treatment’ as used herein refers to both treatment of an existing disease (e.g. a disease or disorder as herein referred to), or prevention of a disease, i.e. prophylaxis. It will therefore be recognized that treatment as referred to herein may, in some embodiments, be prophylactic.

DETAILED DESCRIPTION OF THE INVENTION

The inventors have identified that the expression level of the progranulin transcript can be effectively enhanced by targeting the progranulin precursor-mRNA (pre-mRNA) transcript or the progranulin mature mRNA sequence with antisense oligonucleotides, particularly antisense oligonucleotides which comprise high affinity sugar modified nucleosides, such as high affinity 2′ sugar modified nucleosides, such as LNA nucleosides or 2′-O-methoxyethyl (MOE) nucleosides.

Described herein are target sites present on the human progranulin nucleic acid target, such as a progranulin precursor-mRNA (pre-mRNA) or mature mRNA sequence, which can be targeted by antisense oligonucleotide agonists of progranulin.

The inventors have surprisingly determined that targeting the 5′ UTR and 3′ UTR of the progranulin mature mRNA can be particularly effective.

The 5′ UTR contains upstream start sites (AUG sites), also known as upstream open reading frames (uORFs). Without wishing to be bound by theory, it is considered that the antisense oligonucleotide progranulin agonists of the invention can increase progranulin production by binding to these regions and affecting, such as reducing, protein translation from these upstream AUG sites. This ensures that protein translation is initiated from the downstream canonical start site (ORF), increasing progranulin production.

The 3′ UTR contains binding sites for microRNAs. Without wishing to be bound by theory, it is considered that the antisense oligonucleotide progranulin agonists of the invention may regulate gene expression by binding to these sites in the 3′UTR and preventing microRNA-induced repression of gene expression, leading to increased progranulin production.

Oligonucleotides, such as RNaseH recruiting single stranded antisense oligonucleotides or siRNAs are used extensively in the art to inhibit target RNAs—i.e. are used as antagonists of their complementary nucleic acid target.

The antisense oligonucleotide of the present invention are agonists, i.e. enhance the expression of their complementary target, progranulin nucleic acids, and thereby enhance the expression of progranulin protein. Enhanced progranulin expression is desirable to treat a range of neurological disorders, such as TDP-43 pathologies, or disorders which are characterized by, or caused by progranulin haploinsufficiency.

In certain embodiments the antisense oligonucleotide progranulin agonists of the present invention may enhance the production of their complementary target, progranulin nucleic acids, by at least about 10%. In other embodiments the antisense oligonucleotide progranulin agonists of the present invention may enhance the production of their complementary target, progranulin nucleic acids, by at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50% or more, at least about 60% or more, at least about 70% or more, at least about 80% or more, at least about 90% or more, at least about 100% or more, at least about 200% or more, at least about 300% or more, at least about 400% or more, or at least about 500% or more.

In some embodiments, the antisense oligonucleotide progranulin agonist of the invention or the contiguous nucleotide sequence thereof comprises or consists of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40 contiguous nucleotides in length.

In some embodiments, the entire nucleotide sequence of the antisense oligonucleotide is the contiguous nucleotide sequence.

In some embodiments the contiguous nucleotide sequence is complementary to a 5′UTR region of a human progranulin mature mRNA transcript. The contiguous nucleotide sequence may be fully complementary to a 5′UTR region of a human progranulin mature mRNA transcript. As indicated above, and without wishing to be bound by theory, targeting the 5′UTR may increase progranulin expression by binding to upstream start sites (AUG sites) and affecting, such as reducing, protein translation from these upstream AUG sites. This ensures that protein translation is initiated from the downstream canonical start site (ORF), increasing progranulin production.

In some embodiments the contiguous nucleotide sequence may be complementary to SEQ ID NO 2, SEQ ID NO 689, SEQ ID NO 683, SEQ ID NO 684, SEQ ID NO 685, SEQ ID NO 686, SEQ ID NO 687, SEQ ID NO 688, or a sequence selected from the group consisting of SEQ ID NO 343-586.

In another embodiment the contiguous nucleotide sequence may be complementary to nucleotides 38-246 of SEQ ID NO 1.

In another embodiment the contiguous nucleotide sequence may be fully complementary to SEQ ID NO 2, or SEQ ID NO 689.

In another embodiment the contiguous nucleotide sequence may be fully complementary to a sequence selected from the group consisting of SEQ ID NO 568, SEQ ID NO 571, SEQ ID NO 575, SEQ ID NO 576, SEQ ID NO 577, SEQ ID NO 578, SEQ ID NO 584 & SEQ ID NO 586.

In one embodiment the contiguous nucleotide sequence may a sequence selected from the group consisting of SEQ ID NO 3-342. The invention also contemplates fragements of these contiguous nucleotide sequences, including fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16 or at least 17 contiguous nucleotides thereof.

In certain embodiments the contiguous nucleotide sequence may be selected from the group consisting of SEQ ID NO 105, SEQ ID NO 106, SEQ ID NO 110, SEQ ID NO 113, SEQ ID NO 114, SEQ ID NO 231 and SEQ ID NO 241. The invention also contemplates fragements of these contiguous nucleotide sequences, including fragments of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16 or at least 17 contiguous nucleotides thereof.

In some embodiments the contiguous nucleotide sequence is complementary to a 3′UTR region of a human progranulin mature mRNA transcript. The contiguous nucleotide sequence may be fully complementary to a 3′UTR region of a human progranulin mature mRNA transcript. As indicated above, and without wishing to be bound by theory, the antisense oligonucleotide progranulin agonists of the invention may regulate gene expression by binding to microRNA sites in the 3′UTR and preventing microRNA-induced repression of gene expression, leading to increased progranulin production.

In some embodiments the contiguous nucleotide sequence may be complementary to SEQ ID NO 684, SEQ ID NO 685, SEQ ID NO 686, SEQ ID NO 687, SEQ ID NO 688, or a sequence selected from the group consisting of SEQ ID NO 587-682.

In another embodiment the contiguous nucleotide sequence may be complementary to nucleotides 2039-2346 of SEQ ID NO 1.

In another embodiment the contiguous nucleotide sequence may be fully complementary to SEQ ID NO 684, SEQ ID NO 685, SEQ ID NO 686, SEQ ID NO 687, and SEQ ID NO 688.

In another embodiment the contiguous nucleotide sequence may be fully complementary to a sequence selected from the group consisting of SEQ ID NOs 607, SEQ ID NO 608, SEQ ID NO 609, SEQ ID NO 610, SEQ ID NO 611, SEQ ID NO 612, SEQ ID NO 619, SEQ ID NO 620, SEQ ID NO 633, SEQ ID NO 640, SEQ ID NO 641, SEQ ID NO 645, SEQ ID NO 651, and SEQ ID NO 652.

In some embodiments, the antisense oligonucleotide progranulin agonist or contiguous nucleotide sequence comprises or consists of a sequence selected from the group consisting of sequences SEQ ID NO 3-342. It will be understood that the sequences shown in SEQ ID NO 3-342 may include modified nucleobases which function as the shown nucleobase in base pairing, for example 5-methyl cytosine may be used in place of methyl cytosine. Inosine may be used as a universal base.

In some embodiments, the antisense oligonucleotide progranulin agonist or contiguous nucleotide sequence comprises or consists of 8 to 30 or 8 to 40 nucleotides in length with at least 90% identity, preferably 100% identity, to a sequence selected from the group consisting of SEQ ID NO: 3 to 342. In some embodiments the antisense oligonucleotide progranulin agonist may be 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40 nucleotides in length.

Without wishing to be bound by theory, it is considered that the antisense oligonucleotide progranulin agonists of the invention which bind to target sites outside the 5′ UTR and 3′ UTR regions of the progranulin mature mRNA may increase progranulin protein expression. This increased progranulin protein expression may occur as a result of effects of the antisense oligonucleotide progranulin agonists on secondary regulatory mRNA structures and/or on binding of RNA binding proteins that would otherwise negatively affect protein translation or progranulin mRNA stability.

It is understood that the contiguous nucleobase sequences (motif sequence) can be modified to for example increase nuclease resistance and/or binding affinity to the target nucleic acid.

The pattern in which the modified nucleosides (such as high affinity modified nucleosides) are incorporated into the oligonucleotide sequence is generally termed oligonucleotide design.

The antisense oligonucleotide progranulin agonists of the invention are designed with modified nucleosides and DNA nucleosides. Advantageously, high affinity modified nucleosides are used.

In an embodiment, the oligonucleotide comprises at least 1 modified nucleoside, such as at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15 or at least 16 modified nucleosides.

In an embodiment the oligonucleotide comprises from 1 to 10 modified nucleosides, such as from 2 to 9 modified nucleosides, such as from 3 to 8 modified nucleosides, such as from 4 to 7 modified nucleosides, such as 6 or 7 modified nucleosides. Suitable modifications are described in the “Definitions” section under “modified nucleoside”, “high affinity modified nucleosides”, “sugar modifications”, “2′ sugar modifications” and Locked nucleic acids (LNA)”.

In an embodiment, the antisense oligonucleotide progranulin agonist comprises one or more sugar modified nucleosides, such as 2′ sugar modified nucleosides. Preferably the antisense oligonucleotide progranulin agonist of the invention comprises one or more 2′ sugar modified nucleoside independently selected from the group consisting of 2′-O-alkyl-RNA, 2′-O-methyl-RNA (2′oMe), 2′-alkoxy-RNA, 2′-O-methoxyethyl-RNA (2′MOE), 2′-amino-DNA, 2′-fluoro-DNA, arabino nucleic acid (ANA), 2′-fluoro-ANA and LNA nucleosides. It is advantageous if one or more of the modified nucleoside(s) is a locked nucleic acid (LNA).

In a further embodiment the antisense oligonucleotide progranulin agonist comprises at least one modified internucleoside linkage. Suitable internucleoside modifications are described in the “Definitions” section under “Modified internucleoside linkage”. It is advantageous if at least 75%, such as all, the internucleoside linkages within the contiguous nucleotide sequence are phosphorothioate or boranophosphate internucleoside linkages. In some embodiments all the internucleotide linkages in the contiguous sequence of the oligonucleotide are phosphorothioate linkages.

An antisense oligonucleotide progranulin agonist may have the structure:

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Numbered Paragraphs of the Invention

Aspects of the present invention will now be described by way of numbered paragraphs.

1. An antisense oligonucleotide progranulin agonist, wherein the antisense oligonucleotide is 8-40 nucleotides in length and comprises a contiguous nucleotide sequence of 8-40 nucleotides in length which are fully complementary to a human progranulin pre-mRNA or mRNA transcript, such as SEQ ID NO 1.

2. The antisense oligonucleotide according to paragraph 1, wherein the contiguous nucleotide sequence is of a length of at least 12 nucleotides in length, such as 12-16 or 12-18 nucleotides in length.

3. The antisense oligonucleotide according to paragraph 1 or 2, wherein the contiguous nucleotide sequence is the same length as the antisense oligonucleotide.

4. The antisense oligonucleotide according to any one of paragraphs 1-3, wherein contiguous nucleotide sequence is fully complementary to SEQ ID NO 2, SEQ ID NO 689, SEQ ID NO 683, SEQ ID NO 684, SEQ ID NO 685, SEQ ID NO 686, SEQ ID NO 687, SEQ ID NO 688, or a sequence selected from the group consisting of SEQ ID NO 343-682.

5. The antisense oligonucleotide according to any one of paragraphs 1-4, wherein contiguous nucleotide sequence is fully complementary to a 5′UTR region of a human progranulin mRNA transcript.

6. The antisense oligonucleotide according to any one of paragraphs 1-5, wherein contiguous nucleotide sequence is fully complementary to nucleotides 38-246 of SEQ ID NO 1.

7. The antisense oligonucleotide according to any one of paragraphs 1-6, wherein contiguous nucleotide sequence is fully complementary to SEQ ID NO 2, or SEQ ID NO 689.

8. The antisense oligonucleotide according to any one of paragraphs 1-7, wherein the contiguous nucleotide sequence is fully complementary to a sequence selected from the group consisting of SEQ ID NO 568, 571, 575, 576, 577, 578, 584 & 586.

9. The antisense oligonucleotide according to any one of paragraphs 1-4, wherein contiguous nucleotide sequence is fully complementary to a 3′UTR region of a human progranulin mRNA transcript.

10. The antisense oligonucleotide according to any one of paragraphs 1-4 or 9, wherein contiguous nucleotide sequence is fully complementary to nucleotides 2039-2346 of SEQ ID NO 1.

11. The antisense oligonucleotide according to any one of paragraphs 1-4, 9 or 10 wherein contiguous nucleotide sequence is fully complementary to a sequence selected from the group consisting of SEQ ID NO 684, 685, 683, 686, 687, and 688.

12. The antisense oligonucleotide according to any one of paragraphs 1-4, 9, 10, or 11 wherein contiguous nucleotide sequence is fully complementary to a sequence selected from the group consisting of SEQ ID NOs 607, 608, 609, 610, 611, 612, 619, 620, 633, 640, 641, 645, 651, and 652.

13. The antisense oligonucleotide according to any one of paragraphs 1-12, wherein contiguous nucleotide sequence is a sequence selected from the group consisting of SEQ ID NO 3-342, or at least 8 or at least 10 contiguous nucleotides thereof.

14. The antisense oligonucleotide according to any one of paragraphs 1-13, wherein the oligonucleotide is or comprises an antisense oligonucleotide mixmer or totalmer.

15. The antisense oligonucleotide of any one of paragraphs 1-14, wherein the antisense oligonucleotide or contiguous nucleotide sequence thereof is 10-20 nucleotides in length.

16. The antisense oligonucleotide according to paragraph 1, wherein the antisense oligonucleotide is selected from the group consisting of COMP ID NOs 3-342.

17. A conjugate comprising the antisense oligonucleotide according to any one of paragraphs 1-16, and at least one conjugate moiety covalently attached to said oligonucleotide.

18. A pharmaceutically acceptable salt of the antisense oligonucleotide according to any one of paragraphs 1-16, or the conjugate according to paragraph 17.

19. The pharmaceutically acceptable salt of paragraph 18, wherein the salt is a sodium salt or a potassium salt.

20. A pharmaceutical composition comprising the antisense oligonucleotide of paragraph 1-16 or the conjugate of paragraph 17 and a pharmaceutically acceptable diluent, solvent, carrier, salt and/or adjuvant.

21. A pharmaceutical composition according to paragraph 20, wherein the pharmaceutical composition comprises the antisense oligonucleotide of paragraph 1-16 or the conjugate of paragraph 17, or the pharmaceutically acceptable salt of paragraph 18 or 19 and an aqueous diluent or solvent, such as phosphate buffered saline.

22. An in vivo or in vitro method for enhancing the expression of progranulin in a cell which is expressing progranulin, said method comprising administering an antisense oligonucleotide of any one of paragraphs 1-16 or the conjugate according to paragraph 17, or the salt according to paragraph 18 or 19, or the pharmaceutical composition according to paragraph 20 or 21 in an effective amount to said cell.

23. The method according to paragraph 22, wherein the cell is either a human cell or a mammalian cell.

24. A method for treating or preventing neurological disease comprising administering a therapeutically or prophylactically effective amount of an antisense oligonucleotide of any one of paragraphs 1-16 or the conjugate according to paragraph 17, or the salt according to paragraph 18 or 19, or the pharmaceutical composition according to paragraph 20 or 21 to a subject suffering from or susceptible to neurological disease.

25. The antisense oligonucleotide of any one of paragraphs 1-16 or the conjugate according to paragraph 17, or the salt according to paragraph 18 or 19, or the pharmaceutical composition according to paragraph 20 or 21 for use as a medicament.

26. The an antisense oligonucleotide of any one of paragraphs 1-16 or the conjugate according to paragraph 17, or the salt according to paragraph 18 or 19, or the pharmaceutical composition according to paragraph 20 or 21 for use in the treatment of a neurological disease, such as a TDP-43 pathology.

27. The an antisense oligonucleotide of any one of paragraphs 1-16 or the conjugate according to paragraph 17, or the salt according to paragraph 18 or 19, or the pharmaceutical composition according to paragraph 20 or 21 for use in the treatment of progranulin haploinsufficiency.

28. Use of the antisense oligonucleotide of paragraph 1-16 or the conjugate according to paragraph 17, or the salt according to paragraph 18 or 19, or the pharmaceutical composition according to paragraph 20 or 21 for the preparation of a medicament for treatment or prevention of a neurological disease, such as a TDP-43 pathology.

29. Use of the antisense oligonucleotide of paragraph 1-16 or the conjugate according to paragraph 17, or the salt according to paragraph 18 or 19, or the pharmaceutical composition according to paragraph 20 or 21, for the preparation of a medicament for treatment of progranulin haploinsufficiency.

30. The method or use according to any one of paragraphs 22-29, wherein the method or use is for the treatment of fronto temporal dementia (FTD), neuropathologic frontotemporal lobar degeneration or neuroinflammation.

NUMBERED EMBODIMENTS OF THE INVENTION

Numbered embodiments of the present invention will now be described.

1. An antisense oligonucleotide progranulin agonist, wherein the antisense oligonucleotide is 8-40 nucleotides in length and comprises a contiguous nucleotide sequence of 8-40 nucleotides in length which are complementary to a human progranulin pre-mRNA or mRNA transcript.

2. The antisense oligonucleotide progranulin agonist according to embodiment 1, wherein the contiguous nucleotide sequence is of a length of at least 12 nucleotides in length.

3. The antisense oligonucleotide progranulin agonist according to embodiment 1 or embodiment 2, wherein the contiguous nucleotide sequence is the same length as the antisense oligonucleotide.

4. The antisense oligonucleotide progranulin agonist according to any one of embodiments 1-3, wherein the contiguous nucleotide sequence is complementary to a 5′UTR region of a human progranulin mRNA transcript.

5. The antisense oligonucleotide progranulin agonist according to embodiment 4, wherein the contiguous nucleotide sequence is complementary to SEQ ID NO 2, SEQ ID NO 689, SEQ ID NO 683, or a sequence selected from the group consisting of SEQ ID NO 343-586.

6. The antisense oligonucleotide progranulin agonist according to any one of embodiments 1-5, wherein the contiguous nucleotide sequence is selected from SEQ ID NO 105, SEQ ID NO 106, SEQ ID NO 110, SEQ ID NO 113, SEQ ID NO 114, SEQ ID NO 231 and SEQ ID NO 241 or at least 8 or at least 10 contiguous nucleotides thereof.

7. The antisense oligonucleotide progranulin agonist according to any one of embodiments 1-3, wherein contiguous nucleotide sequence is complementary to a 3′UTR region of a human progranulin mRNA transcript.

8. The antisense oligonucleotide progranulin agonist according to embodiment 7, wherein the contiguous nucleotide sequence is complementary to SEQ ID NO 684, SEQ ID NO 685, SEQ ID NO 686, SEQ ID NO 687, SEQ ID NO 688, or a sequence selected from the group consisting of SEQ ID NO 587-682.

9. The antisense oligonucleotide progranulin agonist according to any one of embodiments 1-8, wherein the antisense oligonucleotide progranulin agonist is or comprises an antisense oligonucleotide mixmer or totalmer.

10. An antisense oligonucleotide progranulin agonist having the structure:

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11. An antisense oligonucleotide progranulin agonist wherein the oligonucleotide is the oligonucleotide compound TgGccAggGatCagGG (SEQ ID NO: 106) wherein capital letters represent beta-D-oxy LNA nucleosides, lowercase letters represent DNA nucleosides, all LNA C are 5-methyl cytosine, and all internucleoside linkages are phosphorothioate internucleoside linkages.

12. An in vivo or in vitro method for enhancing the expression of progranulin in a cell which is expressing progranulin, said method comprising administering an antisense oligonucleotide progranulin agonist according to any one of embodiments 1-11 in an effective amount to said cell.

13. The antisense oligonucleotide progranulin agonist according to any one of embodiments 1-11, for use in the treatment of a neurological disease.

14. The antisense oligonucleotide progranulin agonist or pharmaceutical composition for use in the treatment of a neurological disease according to embodiment 13, wherein the neurological disease is a TDP-43 pathology.

15. The antisense oligonucleotide progranulin agonist according to any one of embodiments 1-11 for use in the treatment of progranulin haploinsufficiency.

EXAMPLES
Example 1

GRN 5′ UTR Luciferase Reporter Constructs

The GRN 5′ UTR sequence (SEQ ID #690) was cloned into the psiCHECK2 plasmid (Promega) immediately in front of the renilla luciferase ATG site using the Q5 site-directed mutagenesis kit (New England Biolabs) according to manufactorer's instruction.

5′ UTR sequence from nucleotide number 38 to 256 according to Homo sapiens granulin precursor (GRN), RefSeq NM_002087.3 (SEQ ID NO 1):

SEQ 690

ID#GGCGAGAGGAAGCAGGGAGGAGAGTGATTTGAGTAGAAAAGAAACA

CAGCATTCCAGGCTGGCCCCACCTCTATATTGATAAGTAGCCAATGGGA

GCGGGTAGCCCTGATCCCTGGCCAATGGAAACTGAGGTAGGCGGGTCAT

CGCGCTGGGGTCTGTAGTCTGAGCGCTACCCGGTTGCTGCTGCCCAAGG

ACCGCGGAGTCGGACGCAGGCAGACC

For the site-directed mutagenesis and insertion of the GRN 5′ UTR the following primers were used:

Forward primer

SEQ ID NO 691

5′-ATGGAAACTGAGGTAGGCGGGTCATCGCGCTGGGGTCTGTAGTCTG

AGCGCTACCCGGTTGCTGCTGCCCAAGGACCGCGGAGTCGGACGCAGGC

AGACCATGGCTTCCAAGGTGTACGACCCCGAGC-3′

and

reverse primer

SEQ ID NO 692

5′-TGGCCAGGGATCAGGGCTACCCGCTCCCATTGGCTACTTATCAATA

TAGAGGTGGGGCCAGCCTGGAATGCTGTGTTTCTTTTCTACTCAAATCA

CTCTCCTCCCTGCTTCCTCTCGCCGGCTAGCCTATAGTGAGTCGTATTA

AGTAC

After transformation of chemical competent bacteria (One Shot TOP10 Chemically Competent E. coli, Thermofisher) and overnight growth on LB agar plates containing ampicillin (imMedia Growth Medium, agar, ampicillin, Thermofisher), single colonies were selected and further grown overnight with constant shaking at 37 Degrees Celcius in LB broth medium containing ampicillin (50 μg/mL) (Thermofisher). Final mini- and midi-prep plasmid purifications were done according to vendors instruction (Qiagen). The inserted 5′ UTR GRN sequences were verified using Sanger sequencing (Eurofins Genomics, Ebersberg, Germany).

Example 2

GRN 3′ UTR Luciferase Reporter Constructs

The GRN 3′ UTR (SEQ ID #2) was cloned into the psiCHECK2 plasmid (Promega) after the renilla luciferase coding sequence using the psiCHECK2 multiple cloning site and the XhoI and NotI restriction sites.

3′ UTR sequence from nucleotide number 2039 to 2346 according to Homo sapiens granulin precursor (GRN), RefSeq NM_002087.3 (SEQ ID NO 1).

SEQ ID#2:

GGGACAGTACTGAAGACTCTGCAGCCCTCGGGACCCCACTCGGAGGGTG

CCCTCTGCTCAGGCCTCCCTAGCACCTCCCCCTAACCAAATTCTCCCTG

GACCCCATTCTGAGCTCCCCATCACCATGGGAGGTGGGGCCTCAATCTA

AGGCCTTCCCTGTCAGAAGGGGGTTGTGGCAAAAGCCACATTACAAGCT

GCCATCCCCTCCCCGTTTCAGTGGACCCTGTGGCCAGGTGCTTTTCCCT

ATCCACAGGGGTGTTTGTGTGTGTGCGCGTGTGCGTTTCAATAAAGTTT

GTACACTTTCTTAA

Double stranded DNA fragment (gBlock, Integrated DNA technologies) containing the GRN 3′ UTR (SEQ ID #2) flanked by XhoI and NotI sites was cut by XhoI and NotI enzymes (New England Biolabs) according to vendors protocol and ligated using T4 Ligase (New England Biolabs) into the previously XhoI/NotI cut psiCHECK2 plasmid.

After transformation of chemical competent bacteria (One Shot® TOP10 Chemically Competent E. coli, Thermofisher) and overnight growth on LB agar plates containing ampicillin (imMedia Growth Medium, agar, ampicilin, Thermofisher), single colonies were selected and further grown overnight with constant shaking at 37 Degrees Celcius in LB broth medium containing ampicillin (50 μg/mL) (Thermofisher). Final mini- and midiprep plasmid purifications were done according to vendors instruction (Qiagen). The inserted 3′ UTR GRN sequence was verified using Sanger sequencing (Eurofins Genomics, Ebersberg, Germany).

Example 3 Luciferase Reporter Assays

The day before transfection, 15000 HeLa cells per well were seeded in 96-well plates (Nunc™ F96 MicroWell™ White Polystyrene Plates) in 100 μL full growth medium. The day at transfection, media is removed and the transfection mixture consisting of 80 μL Opti-MEM Reduced Serum Medium (ThermoFisher Scientific), 6.25 μg/mL Lipofectamine 2000 (ThermoFisher Scientific) and 100 ng psiCHECK2 plasmid with 5′ UTR/3′UTR of GRN is added to each well according to manufactorer's instructions (ThermoFisher Scientific). Shortly after, 20 μL of Opti-MEM Reduced Serum Medium with 500 nM of each antisense oligonucleotide is added to each well for a final concentration of 100 nM. Wells with seeded cells not exposed to transfection reagents are included to correct for background luciferase activity. After 6 hours incubation, transfection mixture is removed from all wells and replaced with full growth medium. The following day, media is removed and replaced with 75 μL PBS, and the Firefly luciferase activity is measured using the Dual-GLo luciferase system (Promega) according to vendors protocol and the EnSight Multimode. Plate Reader (Perkin Elmer). Measurement of The firefly luciferase activity is followed by measurement of the renilla luciferase activity. After correction of the background luciferase activity for each well, the relative luciferase activity is calculated by dividing the Renilla luciferase activity by the firefly luciferase activity for each well to correct for transfection efficiency. Finally, for each antisense oligonucleotides the relative luciferase activity is normalized to PBS transfected cells (PBS=1) and values >1 reflects that the respective antisense oligonucleotides have increased the activity/expression of the renilla luciferase activity.

Example 4

Antisense oligonucleotides were designed for the 5′ UTR from position 38 to 241 according to RefSeq NM_002087.3 (SEQ ID NO 1) with one nucleotide basepair shift as shown in table 1, which also provides the data from the luciferase assay, were a value of greater than 1 indicates an increased expression of progranulin (i.e. progranulin agonist activity of the antisense oligonucleotide), and a value lower than 1 indicates a decreased expression of progranulin (i.e. an inhibition or antagonistic effect, on progranulin expression).

TABLE 1

All the antisense oligonucleotides are designed as 16-mers DNA-LNA mixmers with a phosphorothioate

backbone, LNA at the very 5′ and 3′ position and e.g. LNA for every 2^nd or 3^rd nucleotide (see

Compound table).

RefSeq

Relative

Oligonucleotide
NM_002087.3
Target

luciferase

Compound ID
Sequence Motif
(SEQ ID NO 1)
Site

activity

(See Compound
(nucleobase
Start
End
Sequence
Target
(Relative

SEQ ID
Table)
Sequence)
Position
Position
ID
Site Sequence
to PBS)

SEQ ID 3
COMP ID 3
CCTGCTTCCTCTCGCC
38
53
SEQ ID
GGCGAGAGGAAGCAGG
0,47

343

SEQ ID 4
COMP ID 4
CCCTGCTTCCTCTCGC
39
54
SEQ ID
GCGAGAGGAAGCAGGG
0,60

344

SEQ ID 5
COMP ID 5
TCCCTGCTTCCTCTCG
40
55
SEQ ID
CGAGAGGAAGCAGGGA
0,62

345

SEQ ID 6
COMP ID 6
CTCCCTGCTTCCTCTC
41
56
SEQ ID
GAGAGGAAGCAGGGAG
0,65

346

SEQ ID 7
COMP ID 7
CCTCCCTGCTTCCTCT
42
57
SEQ ID
AGAGGAAGCAGGGAGG
0,85

347

SEQ ID 8
COMP ID 8
TCCTCCCTGCTTCCTC
43
58
SEQ ID
GAGGAAGCAGGGAGGA
0,81

348

SEQ ID 9
COMP ID 9
CTCCTCCCTGCTTCCT
44
59
SEQ ID
AGGAAGCAGGGAGGAG
0,53

349

SEQ ID 10
COMP ID 10
TCTCCTCCCTGCTTCC
45
60
SEQ ID
GGAAGCAGGGAGGAGA
0,80

350

SEQ ID 11
COMP ID 11
CTCTCCTCCCTGCTTC
46
61
SEQ ID
GAAGCAGGGAGGAGAG
0,78

351

SEQ ID 12
COMP ID 12
ACTCTCCTCCCTGCTT
47
62
SEQ ID
AAGCAGGGAGGAGAGT
0,78

352

SEQ ID 13
COMP ID 13
CACTCTCCTCCCTGCT
48
63
SEQ ID
AGCAGGGAGGAGAGTG
0,53

353

SEQ ID 14
COMP ID 14
TCACTCTCCTCCCTGC
49
64
SEQ ID
GCAGGGAGGAGAGTGA
0,66

354

SEQ ID 15
COMP ID 15
ATCACTCTCCTCCCTG
50
65
SEQ ID
CAGGGAGGAGAGTGAT
n.d.

355

SEQ ID 16
COMP ID 16
AATCACTCTCCTCCCT
51
66
SEQ ID
AGGGAGGAGAGTGATT
n.d.

356

SEQ ID 17
COMP ID 17
AAATCACTCTCCTCCC
52
67
SEQ ID
GGGAGGAGAGTGATTT
n.d.

357

SEQ ID 18
COMP ID 18
CAAATCACTCTCCTCC
53
68
SEQ ID
GGAGGAGAGTGATTTG
n.d.

358

SEQ ID 19
COMP ID 19
TCAAATCACTCTCCTC
54
69
SEQ ID
GAGGAGAGTGATTTGA
0,56

359

SEQ ID 20
COMP ID 20
CTCAAATCACTCTCCT
55
70
SEQ ID
AGGAGAGTGATTTGAG
0,58

360

SEQ ID 21
COMP ID 21
ACTCAAATCACTCTCC
56
71
SEQ ID
GGAGAGTGATTTGAGT
0,50

361

SEQ ID 22
COMP ID 22
TACTCAAATCACTCTC
57
72
SEQ ID
GAGAGTGATTTGAGTA
0,44

362

SEQ ID 23
COMP ID 23
CTACTCAAATCACTCT
58
73
SEQ ID
AGAGTGATTTGAGTAG
0,61

363

SEQ ID 24
COMP ID 24
TCTACTCAAATCACTC
59
74
SEQ ID
GAGTGATTTGAGTAGA
0,44

364

SEQ ID 25
COMP ID 25
TTCTACTCAAATCACT
60
75
SEQ ID
AGTGATTTGAGTAGAA
0,47

365

SEQ ID 26
COMP ID 26
TTTCTACTCAAATCAC
61
76
SEQ ID
GTGATTTGAGTAGAAA
0,57

366

SEQ ID 27
COMP ID 27
TTTTCTACTCAAATCA
62
77
SEQ ID
TGATTTGAGTAGAAAA
0,49

367

SEQ ID 28
COMP ID 28
CTTTTCTACTCAAATC
63
78
SEQ ID
GATTTGAGTAGAAAAG
0,54

368

SEQ ID 29
COMP ID 29
TCTTTTCTACTCAAAT
64
79
SEQ ID
ATTTGAGTAGAAAAGA
0,49

369

SEQ ID 30
COMP ID 30
TTCTTTTCTACTCAAA
65
80
SEQ ID
TTTGAGTAGAAAAGAA
0,38

370

SEQ ID 31
COMP ID 31
TTTCTTTTCTACTCAA
66
81
SEQ ID
TTGAGTAGAAAAGAAA
0,59

371

SEQ ID 32
COMP ID 32
GTTTCTTTTCTACTCA
67
82
SEQ ID
TGAGTAGAAAAGAAAC
0,44

372

SEQ ID 33
COMP ID 33
TGTTTCTTTTCTACTC
68
83
SEQ ID
GAGTAGAAAAGAAACA
0,61

373

SEQ ID 34
COMP ID 34
GTGTTTCTTTTCTACT
69
84
SEQ ID
AGTAGAAAAGAAACAC
0,56

374

SEQ ID 35
COMP ID 35
TGTGTTTCTTTTCTAC
70
85
SEQ ID
GTAGAAAAGAAACACA
0,47

375

SEQ ID 36
COMP ID 36
CTGTGTTTCTTTTCTA
71
86
SEQ ID
TAGAAAAGAAACACAG
0,36

376

SEQ ID 37
COMP ID 37
GCTGTGTTTCTTTTCT
72
87
SEQ ID
AGAAAAGAAACACAGC
0,45

377

SEQ ID 38
COMP ID 38
TGCTGTGTTTCTTTTC
73
88
SEQ ID
GAAAAGAAACACAGCA
0,58

378

SEQ ID 39
COMP ID 39
ATGCTGTGTTTCTTTT
74
89
SEQ ID
AAAAGAAACACAGCAT
0,77

379

SEQ ID 40
COMP ID 40
AATGCTGTGTTTCTTT
75
90
SEQ ID
AAAGAAACACAGCATT
0,53

380

SEQ ID 41
COMP ID 41
GAATGCTGTGTTTCTT
76
91
SEQ ID
AAGAAACACAGCATTC
0,73

381

SEQ ID 42
COMP ID 42
GGAATGCTGTGTTTCT
77
92
SEQ ID
AGAAACACAGCATTCC
0,77

382

SEQ ID 43
COMP ID 43
TGGAATGCTGTGTTTC
78
93
SEQ ID
GAAACACAGCATTCCA
0,69

383

SEQ ID 44
COMP ID 44
CTGGAATGCTGTGTTT
79
94
SEQ ID
AAACACAGCATTCCAG
0,63

384

SEQ ID 45
COMP ID 45
CCTGGAATGCTGTGTT
80
95
SEQ ID
AACACAGCATTCCAGG
0,58

385

SEQ ID 46
COMP ID 46
GCCTGGAATGCTGTGT
81
96
SEQ ID
ACACAGCATTCCAGGC
0,57

386

SEQ ID 47
COMP ID 47
AGCCTGGAATGCTGTG
82
97
SEQ ID
CACAGCATTCCAGGCT
0,48

387

SEQ ID 48
COMP ID 48
CAGCCTGGAATGCTGT
83
98
SEQ ID
ACAGCATTCCAGGCTG
0,62

388

SEQ ID 49
COMP ID 49
CCAGCCTGGAATGCTG
84
99
SEQ ID
CAGCATTCCAGGCTGG
0,40

389

SEQ ID 50
COMP ID 50
GCCAGCCTGGAATGCT
85
100
SEQ ID
AGCATTCCAGGCTGGC
0,32

390

SEQ ID 51
COMP ID 51
GGCCAGCCTGGAATGC
86
101
SEQ ID
GCATTCCAGGCTGGCC
0,24

391

SEQ ID 52
COMP ID 52
GGGCCAGCCTGGAATG
87
102
SEQ ID
CATTCCAGGCTGGCCC
0,15

392

SEQ ID 53
COMP ID 53
GGGGCCAGCCTGGAAT
88
103
SEQ ID
ATTCCAGGCTGGCCCC
0,20

393

SEQ ID 54
COMP ID 54
TGGGGCCAGCCTGGAA

104
SEQ ID
TTCCAGGCTGGCCCCA
0,62

394

SEQ ID 55
COMP ID 55
GTGGGGCCAGCCTGGA
90
105
SEQ ID
TCCAGGCTGGCCCCAC
0,54

395

SEQ ID 56
COMP ID 56
GGTGGGGCCAGCCTGG
91
106
SEQ ID
CCAGGCTGGCCCCACC
0,62

396

SEQ ID 57
COMP ID 57
AGGTGGGGCCAGCCTG
92
107
SEQ ID
CAGGCTGGCCCCACCT
0,38

397

SEQ ID 58
COMP ID 58
GAGGTGGGGCCAGCCT
93
108
SEQ ID
AGGCTGGCCCCACCTC
0,46

398

SEQ ID 59
COMP ID 59
AGAGGTGGGGCCAGCC
94
109
SEQ ID
GGCTGGCCCCACCTCT
0,32

399

SEQ ID 60
COMP ID 60
TAGAGGTGGGGCCAGC
95
110
SEQ ID
GCTGGCCCCACCTCTA
0,53

400

SEQ ID 61
COMP ID 61
ATAGAGGTGGGGCCAG
96
111
SEQ ID
CTGGCCCCACCTCTAT
0,37

401

SEQ ID 62
COMP ID 62
TATAGAGGTGGGGCCA
97
112
SEQ ID
TGGCCCCACCTCTATA
0,68

402

SEQ ID 63
COMP ID 63
ATATAGAGGTGGGGCC
98
113
SEQ ID
GGCCCCACCTCTATAT
0,65

403

SEQ ID 64
COMP ID 64
AATATAGAGGTGGGGC
99
114
SEQ ID
GCCCCACCTCTATATT
0,61

404

SEQ ID 65
COMP ID 65
CAATATAGAGGTGGGG
100
115
SEQ ID
CCCCACCTCTATATTG
0,79

405

SEQ ID 66
COMP ID 66
TCAATATAGAGGTGGG
101
116
SEQ ID
CCCACCTCTATATTGA
0,86

406

SEQ ID 67
COMP ID 67
ATCAATATAGAGGTGG
102
117
SEQ ID
CCACCTCTATATTGAT
0,80

407

SEQ ID 68
COMP ID 68
TATCAATATAGAGGTG
103
118
SEQ ID
CACCTCTATATTGATA
0,65

408

SEQ ID 69
COMP ID 69
TTATCAATATAGAGGT
104
119
SEQ ID
ACCTCTATATTGATAA
0,49

409

SEQ ID 70
COMP ID 70
CTTATCAATATAGAGG
105
120
SEQ ID
CCTCTATATTGATAAG
0,93

410

SEQ ID 71
COMP ID 71
ACTTATCAATATAGAG
106
121
SEQ ID
CTCTATATTGATAAGT
0,73

411

SEQ ID 72
COMP ID 72
TACTTATCAATATAGA
107
122
SEQ ID
TCTATATTGATAAGTA
0,87

412

SEQ ID 73
COMP ID 73
CTACTTATCAATATAG
108
123
SEQ ID
CTATATTGATAAGTAG
0,83

413

SEQ ID 74
COMP ID 74
GCTACTTATCAATATA
109
124
SEQ ID
TATATTGATAAGTAGC
0,64

414

SEQ ID 75
COMP ID 75
GGCTACTTATCAATAT
110
125
SEQ ID
ATATTGATAAGTAGCC
0,71

415

SEQ ID 76
COMP ID 76
TGGCTACTTATCAATA
111
126
SEQ ID
TATTGATAAGTAGCCA
0,81

416

SEQ ID 77
COMP ID 77
TTGGCTACTTATCAAT
112
127
SEQ ID
ATTGATAAGTAGCCAA
0,48

417

SEQ ID 78
COMP ID 78
ATTGGCTACTTATCAA
113
128
SEQ ID
TTGATAAGTAGCCAAT
0,88

418

SEQ ID 79
COMP ID 79
CATTGGCTACTTATCA
114
129
SEQ ID
TGATAAGTAGCCAATG
0,72

419

SEQ ID 80
COMP ID 80
CCATTGGCTACTTATC
115
130
SEQ ID
GATAAGTAGCCAATGG
0,53

420

SEQ ID 81
COMP ID 81
CCCATTGGCTACTTAT
116
131
SEQ ID
ATAAGTAGCCAATGGG
0,63

421

SEQ ID 82
COMP ID 82
TCCCATTGGCTACTTA
117
132
SEQ ID
TAAGTAGCCAATGGGA
0,53

422

SEQ ID 83
COMP ID 83
CTCCCATTGGCTACTT
118
133
SEQ ID
AAGTAGCCAATGGGAG
0,57

423

SEQ ID 84
COMP ID 84
GCTCCCATTGGCTACT
119
134
SEQ ID
AGTAGCCAATGGGAGC
0,52

424

SEQ ID 85
COMP ID 85
CGCTCCCATTGGCTAC
120
135
SEQ ID
GTAGCCAATGGGAGCG
0,25

425

SEQ ID 86
COMP ID 86
CCGCTCCCATTGGCTA
121
136
SEQ ID
TAGCCAATGGGAGCGG
0,37

426

SEQ ID 87
COMP ID 87
CCCGCTCCCATTGGCT
122
137
SEQ ID
AGCCAATGGGAGCGGG
0,28

427

SEQ ID 88
COMP ID 88
ACCCGCTCCCATTGGC
123
138
SEQ ID
GCCAATGGGAGCGGGT
0,30

428

SEQ ID 89
COMP ID 89
TACCCGCTCCCATTGG
124
139
SEQ ID
CCAATGGGAGCGGGTA
0,43

429

SEQ ID 90
COMP ID 90
CTACCCGCTCCCATTG
125
140
SEQ ID
CAATGGGAGCGGGTAG
0,38

430

SEQ ID 91
COMP ID 91
GCTACCCGCTCCCATT
126
141
SEQ ID
AATGGGAGCGGGTAGC
0,65

431

SEQ ID 92
COMP ID 92
GGCTACCCGCTCCCAT
127
142
SEQ ID
ATGGGAGCGGGTAGCC
0,51

432

SEQ ID 93
COMP ID 93
GGGCTACCCGCTCCCA
128
143
SEQ ID
TGGGAGCGGGTAGCCC
0,38

433

SEQ ID 94
COMP ID 94
AGGGCTACCCGCTCCC
129
144
SEQ ID
GGGAGCGGGTAGCCCT
0,50

434

SEQ ID 95
COMP ID 95
CAGGGCTACCCGCTCC
130
145
SEQ ID
GGAGCGGGTAGCCCTG
0,45

435

SEQ ID 96
COMP ID 96
TCAGGGCTACCCGCTC
131
146
SEQ ID
GAGCGGGTAGCCCTGA
0,50

436

SEQ ID 97
COMP ID 97
ATCAGGGCTACCCGCT
132
147
SEQ ID
AGCGGGTAGCCCTGAT
0,39

437

SEQ ID 98
COMP ID 98
GATCAGGGCTACCCGC
133
148
SEQ ID
GCGGGTAGCCCTGATC
0,31

438

SEQ ID 99
COMP ID 99
GGATCAGGGCTACCCG
134
149
SEQ ID
CGGGTAGCCCTGATCC
0,32

439

SEQ ID 100
COMP ID 100
GGGATCAGGGCTACCC
135
150
SEQ ID
GGGTAGCCCTGATCCC
0,56

440

SEQ ID 101
COMP ID 101
AGGGATCAGGGCTACC
136
151
SEQ ID
GGTAGCCCTGATCCCT
0,41

441

SEQ ID 102
COMP ID 102
CAGGGATCAGGGCTAC
137
152
SEQ ID
GTAGCCCTGATCCCTG
0,86

442

SEQ ID 103
COMP ID 103
CCAGGGATCAGGGCTA
138
153
SEQ ID
TAGCCCTGATCCCTGG
0,65

443

SEQ ID 104
COMP ID 104
GCCAGGGATCAGGGCT
139
154
SEQ ID
AGCCCTGATCCCTGGC
0,65

444

SEQ ID 105
COMP ID 105
GGCCAGGGATCAGGGC
140
155
SEQ ID
GCCCTGATCCCTGGCC
1,00

445

SEQ ID 106
COMP ID 106
TGGCCAGGGATCAGGG
141
156
SEQ ID
CCCTGATCCCTGGCCA
1,07

446

SEQ ID 107
COMP ID 107
TTGGCCAGGGATCAGG
142
157
SEQ ID
CCTGATCCCTGGCCAA
0,52

447

SEQ ID 108
COMP ID 108
ATTGGCCAGGGATCAG
143
158
SEQ ID
CTGATCCCTGGCCAAT
0,86

448

SEQ ID 109
COMP ID 109
CATTGGCCAGGGATCA
144
159
SEQ ID
TGATCCCTGGCCAATG
0,67

449

SEQ ID 110
COMP ID 110
CCATTGGCCAGGGATC
145
160
SEQ ID
GATCCCTGGCCAATGG
0,54

450

SEQ ID 111
COMP ID 111
TCCATTGGCCAGGGAT
146
161
SEQ ID
ATCCCTGGCCAATGGA
n.d.

451

SEQ ID 112
COMP ID 112
TTCCATTGGCCAGGGA
147
162
SEQ ID
TCCCTGGCCAATGGAA
n.d.

452

SEQ ID 113
COMP ID 113
TTTCCATTGGCCAGGG
148
163
SEQ ID
CCCTGGCCAATGGAAA
n.d.

453

SEQ ID 114
COMP ID 114
GTTTCCATTGGCCAGG
149
164
SEQ ID
CCTGGCCAATGGAAAC
n.d.

454

SEQ ID 115
COMP ID 115
AGTTTCCATTGGCCAG
150
165
SEQ ID
CTGGCCAATGGAAACT
0,43

455

SEQ ID 116
COMP ID 116
CAGTTTCCATTGGCCA
151
166
SEQ ID
TGGCCAATGGAAACTG
0,56

456

SEQ ID 117
COMP ID 117
TCAGTTTCCATTGGCC
152
167
SEQ ID
GGCCAATGGAAACTGA
0,61

457

SEQ ID 118
COMP ID 118
CTCAGTTTCCATTGGC
153
168
SEQ ID
GCCAATGGAAACTGAG
0,71

458

SEQ ID 119
COMP ID 119
CCTCAGTTTCCATTGG
154
169
SEQ ID
CCAATGGAAACTGAGG
1,03

459

SEQ ID 120
COMP ID 120
ACCTCAGTTTCCATTG
155
170
SEQ ID
CAATGGAAACTGAGGT
0,90

460

SEQ ID 121
COMP ID 121
TACCTCAGTTTCCATT
156
171
SEQ ID
AATGGAAACTGAGGTA
0,95

461

SEQ ID 122
COMP ID 122
CTACCTCAGTTTCCAT
157
172
SEQ ID
ATGGAAACTGAGGTAG
0,63

462

SEQ ID 123
COMP ID 123
CCTACCTCAGTTTCCA
158
173
SEQ ID
TGGAAACTGAGGTAGG
0,62

463

SEQ ID 124
COMP ID 124
GCCTACCTCAGTTTCC
159
174
SEQ ID
GGAAACTGAGGTAGGC
0,49

464

SEQ ID 125
COMP ID 125
CGCCTACCTCAGTTTC
160
175
SEQ ID
GAAACTGAGGTAGGCG
1,18

465

SEQ ID 126
COMP ID 126
CCGCCTACCTCAGTTT
161
176
SEQ ID
AAACTGAGGTAGGCGG
0,55

466

SEQ ID 127
COMP ID 127
CCCGCCTACCTCAGTT
162
177
SEQ ID
AACTGAGGTAGGCGGG
0,72

467

SEQ ID 128
COMP ID 128
ACCCGCCTACCTCAGT
163
178
SEQ ID
ACTGAGGTAGGCGGGT
0,44

468

SEQ ID 129
COMP ID 129
GACCCGCCTACCTCAG
164
179
SEQ ID
CTGAGGTAGGCGGGTC
0,42

469

SEQ ID 130
COMP ID 130
TGACCCGCCTACCTCA
165
180
SEQ ID
TGAGGTAGGCGGGTCA
0,28

470

SEQ ID 131
COMP ID 131
ATGACCCGCCTACCTC
166
181
SEQ ID
GAGGTAGGCGGGTCAT
0,19

471

SEQ ID 132
COMP ID 132
GATGACCCGCCTACCT
167
182
SEQ ID
AGGTAGGCGGGTCATC
0,18

472

SEQ ID 133
COMP ID 133
CGATGACCCGCCTACC
168
183
SEQ ID
GGTAGGCGGGTCATCG
0,34

473

SEQ ID 134
COMP ID 134
GCGATGACCCGCCTAC
169
184
SEQ ID
GTAGGCGGGTCATCGC
0,73

474

SEQ ID 135
COMP ID 135
CGCGATGACCCGCCTA
170
185
SEQ ID
TAGGCGGGTCATCGCG
0,66

475

SEQ ID 136
COMP ID 136
GCGCGATGACCCGCCT
171
186
SEQ ID
AGGCGGGTCATCGCGC
0,46

476

SEQ ID 137
COMP ID 137
AGCGCGATGACCCGCC
172
187
SEQ ID
GGCGGGTCATCGCGCT
0,46

477

SEQ ID 138
COMP ID 138
CAGCGCGATGACCCGC
173
188
SEQ ID
GCGGGTCATCGCGCTG
0,53

478

SEQ ID 139
COMP ID 139
CCAGCGCGATGACCCG
174
189
SEQ ID
CGGGTCATCGCGCTGG
0,23

479

SEQ ID 140
COMP ID 140
CCCAGCGCGATGACCC
175
190
SEQ ID
GGGTCATCGCGCTGGG
0,23

480

SEQ ID 141
COMP ID 141
CCCCAGCGCGATGACC
176
191
SEQ ID
GGTCATCGCGCTGGGG
0,42

481

SEQ ID 142
COMP ID 142
ACCCCAGCGCGATGAC
177
192
SEQ ID
GTCATCGCGCTGGGGT
0,30

482

SEQ ID 143
COMP ID 143
GACCCCAGCGCGATGA
178
193
SEQ ID
TCATCGCGCTGGGGTC
0,63

483

SEQ ID 144
COMP ID 144
AGACCCCAGCGCGATG
179
194
SEQ ID
CATCGCGCTGGGGTCT
0,57

484

SEQ ID 145
COMP ID 145
CAGACCCCAGCGCGAT
180
195
SEQ ID
ATCGCGCTGGGGTCTG
0,31

485

SEQ ID 146
COMP ID 146
ACAGACCCCAGCGCGA
181
196
SEQ ID
TCGCGCTGGGGTCTGT
0,29

486

SEQ ID 147
COMP ID 147
TACAGACCCCAGCGCG
182
197
SEQ ID
CGCGCTGGGGTCTGTA
0,34

487

SEQ ID 148
COMP ID 148
CTACAGACCCCAGCGC
183
198
SEQ ID
GCGCTGGGGTCTGTAG
0,32

488

SEQ ID 149
COMP ID 149
ACTACAGACCCCAGCG
184
199
SEQ ID
CGCTGGGGTCTGTAGT
0,34

489

SEQ ID 150
COMP ID 150
GACTACAGACCCCAGC
185
200
SEQ ID
GCTGGGGTCTGTAGTC
0,64

490

SEQ ID 151
COMP ID 151
AGACTACAGACCCCAG
186
201
SEQ ID
CTGGGGTCTGTAGTCT
0,95

491

SEQ ID 152
COMP ID 152
CAGACTACAGACCCCA
187
202
SEQ ID
TGGGGTCTGTAGTCTG
0,52

492

SEQ ID 153
COMP ID 153
TCAGACTACAGACCCC
188
203
SEQ ID
GGGGTCTGTAGTCTGA
0,53

493

SEQ ID 154
COMP ID 154
CTCAGACTACAGACCC
189
204
SEQ ID
GGGTCTGTAGTCTGAG
0,43

494

SEQ ID 155
COMP ID 155
GCTCAGACTACAGACC
190
205
SEQ ID
GGTCTGTAGTCTGAGC
0,33

495

SEQ ID 156
COMP ID 156
CGCTCAGACTACAGAC
191
206
SEQ ID
GTCTGTAGTCTGAGCG
0,43

496

SEQ ID 157
COMP ID 157
GCGCTCAGACTACAGA
192
207
SEQ ID
TCTGTAGTCTGAGCGC
0,46

497

SEQ ID 158
COMP ID 158
AGCGCTCAGACTACAG
193
208
SEQ ID
CTGTAGTCTGAGCGCT
0,80

498

SEQ ID 159
COMP ID 159
TAGCGCTCAGACTACA
194
209
SEQ ID
TGTAGTCTGAGCGCTA
0,47

499

SEQ ID 160
COMP ID 160
GTAGCGCTCAGACTAC
195
210
SEQ ID
GTAGTCTGAGCGCTAC
0,67

500

SEQ ID 161
COMP ID 161
GGTAGCGCTCAGACTA
196
211
SEQ ID
TAGTCTGAGCGCTACC
0,74

501

SEQ ID 162
COMP ID 162
GGGTAGCGCTCAGACT
197
212
SEQ ID
AGTCTGAGCGCTACCC
0,62

502

SEQ ID 163
COMP ID 163
CGGGTAGCGCTCAGAC
198
213
SEQ ID
GTCTGAGCGCTACCCG
0,43

503

SEQ ID 164
COMP ID 164
CCGGGTAGCGCTCAGA
199
214
SEQ ID
TCTGAGCGCTACCCGG
0,38

504

SEQ ID 165
COMP ID 165
ACCGGGTAGCGCTCAG
200
215
SEQ ID
CTGAGCGCTACCCGGT
0,45

505

SEQ ID 166
COMP ID 166
AACCGGGTAGCGCTCA
201
216
SEQ ID
TGAGCGCTACCCGGTT
0,61

506

SEQ ID 167
COMP ID 167
CAACCGGGTAGCGCTC
202
217
SEQ ID
GAGCGCTACCCGGTTG
0,56

507

SEQ ID 168
COMP ID 168
GCAACCGGGTAGCGCT
203
218
SEQ ID
AGCGCTACCCGGTTGC
0,50

508

SEQ ID 169
COMP ID 169
AGCAACCGGGTAGCGC
204
219
SEQ ID
GCGCTACCCGGTTGCT
0,35

509

SEQ ID 170
COMP ID 170
CAGCAACCGGGTAGCG
205
220
SEQ ID
CGCTACCCGGTTGCTG
0,21

510

SEQ ID 171
COMP ID 171
GCAGCAACCGGGTAGC
206
221
SEQ ID
GCTACCCGGTTGCTGC
0,19

511

SEQ ID 172
COMP ID 172
AGCAGCAACCGGGTAG
207
222
SEQ ID
CTACCCGGTTGCTGCT
0,26

512

SEQ ID 173
COMP ID 173
CAGCAGCAACCGGGTA
208
223
SEQ ID
TACCCGGTTGCTGCTG
0,22

513

SEQ ID 174
COMP ID 174
GCAGCAGCAACCGGGT
209
224
SEQ ID
ACCCGGTTGCTGCTGC
0,42

514

SEQ ID 175
COMP ID 175
GGCAGCAGCAACCGGG
210
225
SEQ ID
CCCGGTTGCTGCTGCC
0,41

515

SEQ ID 176
COMP ID 176
GGGCAGCAGCAACCGG
211
226
SEQ ID
CCGGTTGCTGCTGCCC
0,44

516

SEQ ID 177
COMP ID 177
TGGGCAGCAGCAACCG
212
227
SEQ ID
CGGTTGCTGCTGCCCA
0,42

517

SEQ ID 178
COMP ID 178
TTGGGCAGCAGCAACC
213
228
SEQ ID
GGTTGCTGCTGCCCAA
0,36

518

SEQ ID 179
COMP ID 179
CTTGGGCAGCAGCAAC
214
229
SEQ ID
GTTGCTGCTGCCCAAG
0,28

519

SEQ ID 180
COMP ID 180
CCTTGGGCAGCAGCAA
215
230
SEQ ID
TTGCTGCTGCCCAAGG
0,31

520

SEQ ID 181
COMP ID 181
TCCTTGGGCAGCAGCA
216
231
SEQ ID
TGCTGCTGCCCAAGGA
0,26

521

SEQ ID 182
COMP ID 182
GTCCTTGGGCAGCAGC
217
232
SEQ ID
GCTGCTGCCCAAGGAC
0,60

522

SEQ ID 183
COMP ID 183
GGTCCTTGGGCAGCAG
218
233
SEQ ID
CTGCTGCCCAAGGACC
0,39

523

SEQ ID 184
COMP ID 184
CGGTCCTTGGGCAGCA
219
234
SEQ ID
TGCTGCCCAAGGACCG
0,30

524

SEQ ID 185
COMP ID 185
GCGGTCCTTGGGCAGC
220
235
SEQ ID
GCTGCCCAAGGACCGC
0,44

525

SEQ ID 186
COMP ID 186
CGCGGTCCTTGGGCAG
221
236
SEQ ID
CTGCCCAAGGACCGCG
0,21

526

SEQ ID 187
COMP ID 187
CCGCGGTCCTTGGGCA
222
237
SEQ ID
TGCCCAAGGACCGCGG
0,25

527

SEQ ID 188
COMP ID 188
TCCGCGGTCCTTGGGC
223
238
SEQ ID
GCCCAAGGACCGCGGA
0,21

528

SEQ ID 189
COMP ID 189
CTCCGCGGTCCTTGGG
224
239
SEQ ID
CCCAAGGACCGCGGAG
0,25

529

SEQ ID 190
COMP ID 190
ACTCCGCGGTCCTTGG
225
240
SEQ ID
CCAAGGACCGCGGAGT
0,55

530

SEQ ID 191
COMP ID 191
GACTCCGCGGTCCTTG
226
241
SEQ ID
CAAGGACCGCGGAGTC
0,33

531

SEQ ID 192
COMP ID 192
CGACTCCGCGGTCCTT
227
242
SEQ ID
AAGGACCGCGGAGTCG
0,49

532

SEQ ID 193
COMP ID 193
CCGACTCCGCGGTCCT
228
243
SEQ ID
AGGACCGCGGAGTCGG
0,23

533

SEQ ID 194
COMP ID 194
TCCGACTCCGCGGTCC
229
244
SEQ ID
GGACCGCGGAGTCGGA
0,20

534

SEQ ID 195
COMP ID 195
GTCCGACTCCGCGGTC
230
245
SEQ ID
GACCGCGGAGTCGGAC
0,25

535

SEQ ID 196
COMP ID 196
CGTCCGACTCCGCGGT
231
246
SEQ ID
ACCGCGGAGTCGGACG
0,55

536

SEQ ID 197
COMP ID 197
GCGTCCGACTCCGCGG
232
247
SEQ ID
CCGCGGAGTCGGACGC
0,41

537

SEQ ID 198
COMP ID 198
TGCGTCCGACTCCGCG
233
248
SEQ ID
CGCGGAGTCGGACGCA
0,33

538

SEQ ID 199
COMP ID 199
CTGCGTCCGACTCCGC
234
249
SEQ ID
GCGGAGTCGGACGCAG
0,180,47

539

SEQ ID 200
COMP ID 200
CCTGCGTCCGACTCCG
235
250
SEQ ID
CGGAGTCGGACGCAGG
0,140,60

540

SEQ ID 201
COMP ID 201
GCCTGCGTCCGACTCC
236
251
SEQ ID
GGAGTCGGACGCAGGC
0,150,62

541

SEQ ID 202
COMP ID 202
TGCCTGCGTCCGACTC
237
252
SEQ ID
GAGTCGGACGCAGGCA
0,230,65

542

SEQ ID 203
COMP ID 203
CTGCCTGCGTCCGACT
238
253
SEQ ID
AGTCGGACGCAGGCAG
0,270,85

543

SEQ ID 204
COMP ID 204
TCTGCCTGCGTCCGAC
239
254
SEQ ID
GTCGGACGCAGGCAGA
0,270,81

544

SEQ ID 205
COMP ID 205
GTCTGCCTGCGTCCGA
240
255
SEQ ID
TCGGACGCAGGCAGAC
0,220,53

545

SEQ ID 206
COMP ID 206
GGTCTGCCTGCGTCCG
241
256
SEQ ID
CGGACGCAGGCAGACC
0,330,80

546

Example 5

Antisense oligonucleotides were designed for the 5′ UTR from position 119 to 158 according to RefSeq NM_002087.3 (SEQ ID NO 1) with one nucleotide basepair shift as shown in table 2, which also provides the data from the luciferase assay, were a value of greater than 1 indicates an increased expression of progranulin (i.e. progranulin agonist activity of the antisense oligonucleotide), and a value lower than 1 indicates a decreased expression of progranulin (i.e. an inhibition or antagonistic effect, on progranulin expression).

The results from example 4 and 5 show that antisense oligonucleotide agonism was identified for several compounds targeting the progranulin 5′UTR, particularly compounds with a contiguous nucleotide complementary to nucleotides 1-229 of SEQ ID NO 1, such as compounds complementary to SEQ ID NO 445, SEQ ID NO: 446, SEQ ID NO: 459, SEQ ID NO 465, SEQ ID NO 683, SEQ ID NO 568, SEQ ID NO 571, SEQ ID NO 575, SEQ ID NO 576, SEQ ID NO 577, SEQ ID NO 578, SEQ ID NO 584, & SEQ ID NO 586.

Compounds 105, 106, 119, 125, 117, 228, 231, 235-8, 244 and 246 were identified as having progranulin agonist activity in the luciferase assay.

TABLE 2

All the antisense oligonucleotides are designed as 18-mers DNA-LNA mixmers with a phosphorothioate

backbone, DNA-LNA mixmers with a phosphorothioate backbone, LNA at the very 5′ and 3′ position and

e.g. LNA for every 2^nd or 3^rd nucleotide (see Compound table).

Compound

RefSeq

Relative

ID Number-

NM_002087.3
Target

luciferase

See
Oligonucleotide
(SEQ ID NO 1)
Site

activity

Compound
Sequence Motif
Start
End
Sequence
Target
Relative

SEQ ID
Table
(nucleobase Sequence)
Position
Position
ID
Site Sequence
to PBS)

SEQ
COMP ID
GCTCCCATTGGCTACTTA
119
136
SEQ ID
TAAGTAGCCAATGGGAGC
0,32

ID#207
207

547

SEQ
COMP ID
CGCTCCCATTGGCTACTT
120
137
SEQ ID
AAGTAGCCAATGGGAGCG
0,22

ID#208
208

548

SEQ
COMP ID
CCGCTCCCATTGGCTACT
121
138
SEQ ID
AGTAGCCAATGGGAGCGG
0,19

ID#209
209

549

SEQ
COMP ID
CCCGCTCCCATTGGCTAC
122
139
SEQ ID
GTAGCCAATGGGAGCGGG
0,24

ID#210
210

550

SEQ
COMP ID
ACCCGCTCCCATTGGCTA
123
140
SEQ ID
TAGCCAATGGGAGCGGGT
0,37

ID#211
211

551

SEQ
COMP ID
TACCCGCTCCCATTGGCT
124
141
SEQ ID
AGCCAATGGGAGCGGGTA
0,38

ID#212
212

552

SEQ
COMP ID
CTACCCGCTCCCATTGGC
125
142
SEQ ID
GCCAATGGGAGCGGGTAG
0,39

ID#213
213

553

SEQ
COMP ID
GCTACCCGCTCCCATTGG
126
143
SEQ ID
CCAATGGGAGCGGGTAGC
0,47

ID#214
214

554

SEQ
COMP ID
GGCTACCCGCTCCCATTG
127
144
SEQ ID
CAATGGGAGCGGGTAGCC
0,55

ID#215
215

555

SEQ
COMP ID
GGGCTACCCGCTCCCATT
128
145
SEQ ID
AATGGGAGCGGGTAGCCC
0,53

ID#216
216

556

SEQ
COMP ID
AGGGCTACCCGCTCCCAT
129
146
SEQ ID
ATGGGAGCGGGTAGCCCT
0,56

ID#217
217

557

SEQ
COMP ID
CAGGGCTACCCGCTCCCA
130
147
SEQ ID
TGGGAGCGGGTAGCCCTG
0,49

ID#218
218

558

SEQ
COMP ID
TCAGGGCTACCCGCTCCC
131
148
SEQ ID
GGGAGCGGGTAGCCCTGA
0,58

ID#219
219

559

SEQ
COMP ID
ATCAGGGCTACCCGCTCC
132
149
SEQ ID
GGAGCGGGTAGCCCTGAT
0,48

ID#220
220

560

SEQ
COMP ID
GATCAGGGCTACCCGCTC
133
150
SEQ ID
GAGCGGGTAGCCCTGATC
0,49

ID#221
221

561

SEQ
COMP ID
GGATCAGGGCTACCCGCT
134
151
SEQ ID
AGCGGGTAGCCCTGATCC
0,38

ID#222
222

562

SEQ
COMP ID
GGGATCAGGGCTACCCGC
135
152
SEQ ID
GCGGGTAGCCCTGATCCC
0,33

ID#223
223

563

SEQ
COMP ID
AGGGATCAGGGCTACCCG
136
153
SEQ ID
CGGGTAGCCCTGATCCCT
0,36

ID#224
224

564

SEQ
COMP ID
CAGGGATCAGGGCTACCC
137
154
SEQ ID
GGGTAGCCCTGATCCCTG
0,48

ID#225
225

565

SEQ
COMP ID
CCAGGGATCAGGGCTACC
138
155
SEQ ID
GGTAGCCCTGATCCCTGG
0,69

ID#226
226

566

SEQ
COMP ID
GCCAGGGATCAGGGCTAC
139
156
SEQ ID
GTAGCCCTGATCCCTGGC
0,94

ID#227
227

567

SEQ
COMP ID
GGCCAGGGATCAGGGCTA
140
157
SEQ ID
TAGCCCTGATCCCTGGCC
1,15

ID#228
228

568

SEQ
COMP ID
TGGCCAGGGATCAGGGCT
141
158
SEQ ID
AGCCCTGATCCCTGGCCA
0,92

ID#229
229

569

SEQ
COMP ID
TTGGCCAGGGATCAGGGC
142
159
SEQ ID
GCCCTGATCCCTGGCCAA
0,85

ID#230
230

570

SEQ
COMP ID
ATTGGCCAGGGATCAGGG
143
160
SEQ ID
CCCTGATCCCTGGCCAAT
1,12

ID#231
231

571

SEQ
COMP ID
CATTGGCCAGGGATCAGG
144
161
SEQ ID
CCTGATCCCTGGCCAATG
0,72

ID#232
232

572

SEQ
COMP ID
CCATTGGCCAGGGATCAG
145
162
SEQ ID
CTGATCCCTGGCCAATGG
0,75

ID#233
233

573

SEQ
COMP ID
TCCATTGGCCAGGGATCA
146
163
SEQ ID
TGATCCCTGGCCAATGGA
0,97

ID#234
234

574

SEQ
COMP ID
TTCCATTGGCCAGGGATC
147
164
SEQ ID
GATCCCTGGCCAATGGAA
1,22

ID#235
235

575

SEQ
COMP ID
TTTCCATTGGCCAGGGAT
148
165
SEQ ID
ATCCCTGGCCAATGGAAA
1,13

ID#236
236

576

SEQ
COMP ID
GTTTCCATTGGCCAGGGA
149
166
SEQ ID
TCCCTGGCCAATGGAAAC
1,01

ID#237
237

577

SEQ
COMP ID
AGTTTCCATTGGCCAGGG
150
167
SEQ ID
CCCTGGCCAATGGAAACT
1,09

ID#238
238

578

SEQ
COMP ID
CAGTTTCCATTGGCCAGG
151
168
SEQ ID
CCTGGCCAATGGAAACTG
0,79

ID#239
239

579

SEQ
COMP ID
TCAGTTTCCATTGGCCAG
152
169
SEQ ID
CTGGCCAATGGAAACTGA
0,69

ID#240
240

580

SEQ
COMP ID
CTCAGTTTCCATTGGCCA
153
170
SEQ ID
TGGCCAATGGAAACTGAG
0,59

ID#241
241

581

SEQ
COMP ID
CCTCAGTTTCCATTGGCC
154
171
SEQ ID
GGCCAATGGAAACTGAGG
0,39

ID#242
242

582

SEQ
COMP ID
ACCTCAGTTTCCATTGGC
155
172
SEQ ID
GCCAATGGAAACTGAGGT
0,95

ID#243
243

583

SEQ
COMP ID
TACCTCAGTTTCCATTGG
156
173
SEQ ID
CCAATGGAAACTGAGGTA
1,12

ID#244
244

584

SEQ
COMP ID
CTACCTCAGTTTCCATTG
157
174
SEQ ID
CAATGGAAACTGAGGTAG
1,00

ID#245
245

585

SEQ
COMP ID
CCTACCTCAGTTTCCATT
158
175
SEQ ID
AATGGAAACTGAGGTAGG
1,26

ID#246
246

586

Example 6

Antisense oligonucleotides were designed for the 3′ UTR from position 2044 to 2346 according to RefSeq NM_002807.3 with three nucleotide basepar shift as shown in table 3 which also provides the data from the luciferase assay, were a value of greater than 1 indicates an increased expression of progranulin (i.e. progranulin agonist activity of the antisense oligonucleotide), and a value lower than 1 indicates a decreased expression of progranulin (i.e. an inhibition or antagonistic effect, on progranulin expression).

The data shows antisense oligonucleotide antisense oligonucleotides with progranulin agonist activity that are complementary to the 3′UTR region of a human progranulin mRNA transcript were identified, for example compounds with a contiguous nucleotide sequence which is complementary to a sequence selected from the group consisting of SEQ ID NO 684, 685, 683, 686, 687, and 688, such as compounds with a contiguous nucleotide sequence which is complementary to a sequence selected from the group consisting of 607, 608, 609, 610, 611, 612, 619, 620, 633, 640, 641,645, 651, and 652.

Compounds 263, 267, 269-272, 279, 280, 293, 300, 301, 305, 311, 312 and 327 were identified as exhibiting progranulin agonist activity in the luciferase assay system used.

TABLE 3

All the antisense oligonucleotides are designed as 18-mers DNA-LNA mixmers with a phosphorothioate

backbone, DNA-LNA mixmers with a phosphorothioate backbone, LNA at the very 5′ and 3′ position and

e.g. LNA for every 2^nd or 3^rd nucleotide (see Compound table).

RefSeq

Relative

NM_002087.3
Target

luciferase

Compound
Oligonucleotide
(SEQ ID NO 1)
Site

activity

SEQ
ID # (see
Sequence Motif
Start
End
Sequence
Target
Relative

ID
Compound
(nucleobase Sequence)
Position
Position
ID
Site Sequence
to PBS)

SEQ
COMP ID
5′-TGCAGAGTCTTCAGTACT-3′
2044
2061
SEQ ID
AGTACTGAAGACTCTGCA
0,46

ID
247

587

#247

SEQ
COMP ID
5′-GGCTGCAGAGTCTTCAGT-3′
2047
2064
SEQ ID
ACTGAAGACTCTGCAGCC
0,25

ID
248

588

#248

SEQ
COMP ID
5′-GAGGGCTGCAGAGTCTTC-3′
2050
2067
SEQ ID
GAAGACTCTGCAGCCCTC
0,35

ID
249

589

#249

SEQ
COMP ID
5′-CCCGAGGGCTGCAGAGTC-3′
2053
2070
SEQ ID
GACTCTGCAGCCCTCGGG
0,65

ID
250

590

#250

SEQ
COMP ID
5′-GGTCCCGAGGGCTGCAGA-3′
2056
2073
SEQ ID
TCTGCAGCCCTCGGGACC
0,69

ID
251

591

#251

SEQ
COMP ID
5′-TGGGGTCCCGAGGGCTGC-3′
2059
2076
SEQ ID
GCAGCCCTCGGGACCCCA
0,37

ID
252

592

#252

SEQ
COMP ID
5′-GAGTGGGGTCCCGAGGGC-3′
2062
2079
SEQ ID
GCCCTCGGGACCCCACTC
0,77

ID
253

593

#253

SEQ
COMP ID
5′-TCCGAGTGGGGTCCCGAG-3′
2065
2082
SEQ ID
CTCGGGACCCCACTCGGA
0,75

ID
254

594

#254

SEQ
COMP ID
5′-CCCTCCGAGTGGGGTCCC-3′
2068
2085
SEQ ID
GGGACCCCACTCGGAGGG
0,67

ID
255

595

#255

SEQ
COMP ID
5′-GCACCCTCCGAGTGGGGT-3′
2071
2088
SEQ ID
ACCCCACTCGGAGGGTGC
0,57

ID
256

596

#256

SEQ
COMP ID
5′-AGGGCACCCTCCGAGTGG-3′
2074
2091
SEQ ID
CCACTCGGAGGGTGCCCT
0,78

ID
257

597

#257

SEQ
COMP ID
5′-CAGAGGGCACCCTCCGAG-3′
2077
2094
SEQ ID
CTCGGAGGGTGCCCTCTG
0,92

ID
258

598

#258

SEQ
COMP ID
5′-GAGCAGAGGGCACCCTCC-3′
2080
2097
SEQ ID
GGAGGGTGCCCTCTGCTC
0,29

ID
259

599

#259

SEQ
COMP ID
5′-CCTGAGCAGAGGGCACCC-3′
2083
2100
SEQ ID
GGGTGCCCTCTGCTCAGG
0,63

ID
260

600

#260

SEQ
COMP ID
5′-AGGCCTGAGCAGAGGGCA-3′
2086
2103
SEQ ID
TGCCCTCTGCTCAGGCCT
0,56

ID
261

601

#261

SEQ
COMP ID
5′-GGGAGGCCTGAGCAGAGG-3′
2089
2106
SEQ ID
CCTCTGCTCAGGCCTCCC
0,74

ID
262

602

#262

SEQ
COMP ID
5′-CTAGGGAGGCCTGAGCAG-3′
2092
2109
SEQ ID
CTGCTCAGGCCTCCCTAG
1,13

ID
263

603

#263

SEQ
COMP ID
5′-GTGCTAGGGAGGCCTGAG-3′
2095
2112
SEQ ID
CTCAGGCCTCCCTAGCAC
0,99

ID
264

604

#264

SEQ
COMP ID
5′-GAGGTGCTAGGGAGGCCT-3′
2098
2115
SEQ ID
AGGCCTCCCTAGCACCTC
0,83

ID
265

605

#265

SEQ
COMP ID
5′-GGGGAGGTGCTAGGGAGG-3′
2101
2118
SEQ ID
CCTCCCTAGCACCTCCCC
0,89

ID
266

606

#266

SEQ
COMP ID
5′-TAGGGGGAGGTGCTAGGG-3′
2104
2121
SEQ ID
CCCTAGCACCTCCCCCTA
1,27

ID
267

607

#267

SEQ
COMP ID
5′-GGTTAGGGGGAGGTGCTA-3′
2107
2124
SEQ ID
TAGCACCTCCCCCTAACC
0,58

ID
268

608

#268

SEQ
COMP ID
5′-TTTGGTTAGGGGGAGGTG-3′
2110
2127
SEQ ID
CACCTCCCCCTAACCAAA
1,09

ID
269

609

#269

SEQ
COMP ID
5′-GAATTTGGTTAGGGGGAG-3′
2113
2130
SEQ ID
CTCCCCCTAACCAAATTC
1,24

ID
270

610

#270

SEQ
COMP ID
5′-GGAGAATTTGGTTAGGGG-3′
2116
2133
SEQ ID
CCCCTAACCAAATTCTCC
1,05

ID
271

611

#271

SEQ
COMP ID
5′-CAGGGAGAATTTGGTTAG-3′
2119
2136
SEQ ID
CTAACCAAATTCTCCCTG
1,04

ID
272

612

#272

SEQ
COMP ID
5′-GTCCAGGGAGAATTTGGT-3′
2122
2139
SEQ ID
ACCAAATTCTCCCTGGAC
0,94

ID
273

613

#273

SEQ
COMP ID
5′-GGGGTCCAGGGAGAATTT-3′
2125
2142
SEQ ID
AAATTCTCCCTGGACCCC
0,89

ID
274

614

#274

SEQ
COMP ID
5′-AATGGGGTCCAGGGAGAA-3′
2128
2145
SEQ ID
TTCTCCCTGGACCCCATT
0,99

ID
275

615

#275

SEQ
COMP ID
5′-CAGAATGGGGTCCAGGGA-3′
2131
2148
SEQ ID
TCCCTGGACCCCATTCTG
0,60

ID
276

616

#276

SEQ
COMP ID
5′-GCTCAGAATGGGGTCCAG-3′
2134
2151
SEQ ID
CTGGACCCCATTCTGAGC
0,52

ID
277

617

#277

SEQ
COMP ID
5′-GGAGCTCAGAATGGGGTC-3′
2137
2154
SEQ ID
GACCCCATTCTGAGCTCC
0,91

ID
278

618

#278

SEQ
COMP ID
5′-TGGGGAGCTCAGAATGGG-3′
2140
2157
SEQ ID
CCCATTCTGAGCTCCCCA
1,14

ID
279

619

#279

SEQ
COMP ID
5′-TGATGGGGAGCTCAGAAT-3′
2143
2160
SEQ ID
ATTCTGAGCTCCCCATCA
1,11

ID
280

620

#280

SEQ
COMP ID
5′-TGGTGATGGGGAGCTCAG-3′
2146
2163
SEQ ID
CTGAGCTCCCCATCACCA
0,97

ID
281

621

#281

SEQ
COMP ID
5′-CCATGGTGATGGGGAGCT-3′
2149
2166
SEQ ID
AGCTCCCCATCACCATGG
0,97

ID
282

622

#282

SEQ
COMP ID
5′-CTCCCATGGTGATGGGGA-3′
2152
2169
SEQ ID
TCCCCATCACCATGGGAG
0,81

ID
283

623

#283

SEQ
COMP ID
5′-CACCTCCCATGGTGATGG-3′
2155
2172
SEQ ID
CCATCACCATGGGAGGTG
0,69

ID
284

624

#284

SEQ
COMP ID
5′-CCCCACCTCCCATGGTGA-3′
2158
2175
SEQ ID
TCACCATGGGAGGTGGGG
0,69

ID
285

625

#285

SEQ
COMP ID
5′-AGGCCCCACCTCCCATGG-3′
2161
2178
SEQ ID
CCATGGGAGGTGGGGCCT
0,58

ID
286

626

#286

SEQ
COMP ID
5′-TTGAGGCCCCACCTCCCA-3′
2164
2181
SEQ ID
TGGGAGGTGGGGCCTCAA
0,47

ID
287

627

#287

SEQ
COMP ID
5′-AGATTGAGGCCCCACCTC-3′
2167
2184
SEQ ID
GAGGTGGGGCCTCAATCT
0,59

ID
288

628

#288

SEQ
COMP ID
5′-CTTAGATTGAGGCCCCAC-3′
2170
2187
SEQ ID
GTGGGGCCTCAATCTAAG
0,38

ID
289

629

#289

SEQ
COMP ID
5′-GGCCTTAGATTGAGGCCC-3′
2173
2190
SEQ ID
GGGCCTCAATCTAAGGCC
0,43

ID
290

630

#290

SEQ
COMP ID
5′-GAAGGCCTTAGATTGAGG-3′
2176
2193
SEQ ID
CCTCAATCTAAGGCCTTC
0,76

ID
291

631

#291

SEQ
COMP ID
5′-AGGGAAGGCCTTAGATTG-3′
2179
2196
SEQ ID
CAATCTAAGGCCTTCCCT
0,86

ID
292

632

#292

SEQ
COMP ID
5′-GACAGGGAAGGCCTTAGA-3′
2182
2199
SEQ ID
TCTAAGGCCTTCCCTGTC
1,04

ID
293

633

#293

SEQ
COMP ID
5′-TCTGACAGGGAAGGCCTT-3′
2185
2202
SEQ ID
AAGGCCTTCCCTGTCAGA
0,81

ID
294

634

#294

SEQ
COMP ID
5′-CCTTCTGACAGGGAAGGC-3′
2188
2205
SEQ ID
GCCTTCCCTGTCAGAAGG
0,89

ID
295

635

#295

SEQ
COMP ID
5′-CCCCCTTCTGACAGGGAA-3′
2191
2208
SEQ ID
TTCCCTGTCAGAAGGGGG
0,71

ID
296

636

#296

SEQ
COMP ID
5′-CAACCCCCTTCTGACAGG-3′
2194
2211
SEQ ID
CCTGTCAGAAGGGGGTTG
0,89

ID
297

637

#297

SEQ
COMP ID
5′-CCACAACCCCCTTCTGAC-3′
2197
2214
SEQ ID
GTCAGAAGGGGGTTGTGG
0,42

ID
298

638

#298

SEQ
COMP ID
5′-TTGCCACAACCCCCTTCT-3′
2200
2217
SEQ ID
AGAAGGGGGTTGTGGCAA
0,88

ID
299

639

#299

SEQ
COMP ID
5′-CTTTTGCCACAACCCCCT-3′
2203
2220
SEQ ID
AGGGGGTTGTGGCAAAAG
1,16

ID
300

640

#300

SEQ
COMP ID
5′-TGGCTTTTGCCACAACCC-3′
2206
2223
SEQ ID
GGGTTGTGGCAAAAGCCA
1,08

ID
301

641

#301

SEQ
COMP ID
5′-ATGTGGCTTTTGCCACAA-3′
2209
2226
SEQ ID
TTGTGGCAAAAGCCACAT
1,01

ID
302

642

#302

SEQ
COMP ID
5′-GTAATGTGGCTTTTGCCA-3′
2212
2229
SEQ ID
TGGCAAAAGCCACATTAC
0,55

ID
303

643

#303

SEQ
COMP ID
5′-CTTGTAATGTGGCTTTTG-3′
2215
2232
SEQ ID
CAAAAGCCACATTACAAG
1,01

ID
304

644

#304

SEQ
COMP ID
5′-CAGCTTGTAATGTGGCTT-3′
2218
2235
SEQ ID
AAGCCACATTACAAGCTG
1,50

ID
305

645

#305

SEQ
COMP ID
5′-TGGCAGCTTGTAATGTGG-3′
2221
2238
SEQ ID
CCACATTACAAGCTGCCA
0,96

ID
306

646

#306

SEQ
COMP ID
5′-GGATGGCAGCTTGTAATG-3′
2224
2241
SEQ ID
CATTACAAGCTGCCATCC
0,74

ID
307

647

#307

SEQ
COMP ID
5′-AGGGGATGGCAGCTTGTA-3′
2227
2244
SEQ ID
TACAAGCTGCCATCCCCT
0,84

ID
308

648

#308

SEQ
COMP ID
5′-GGGAGGGGATGGCAGOTT-3′
2230
2247
SEQ ID
AAGCTGCCATCCCCTCCC
0,63

ID
309

649

#309

SEQ
COMP ID
5′-ACGGGGAGGGGATGGCAG-3
2233
2250
SEQ ID
CTGCCATCCCCTCCCCGT
0,71

ID
310

650

#310

SEQ
COMP ID
5′-GAAACGGGGAGGGGATGG-3′
2236
2253
SEQ ID
CCATCCCCTCCCCGTTTC
1,06

ID
311

651

#311

SEQ
COMP ID
5′-ACTGAAACGGGGAGGGGA-3′
2239
2256
SEQ ID
TCCCCTCCCCGTTTCAGT
1,08

ID
312

652

#312

SEQ
COMP ID
5′-TCCACTGAAACGGGGAGG-3′
2242
2259
SEQ ID
CCTCCCCGTTTCAGTGGA
0,53

ID
313

653

#313

SEQ
COMP ID
5′-GGGTCCACTGAAACGGGG-3′
2245
2262
SEQ ID
CCCCGTTTCAGTGGACCC
0,93

ID
314

654

#314

SEQ
COMP ID
5′-ACAGGGTCCACTGAAACG-3′
2248
2265
SEQ ID
CGTTTCAGTGGACCCTGT
0,49

ID
315

655

#315

SEQ
COMP ID
5′-GCCACAGGGTCCACTGAA-3′
2251
2268
SEQ ID
TTCAGTGGACCCTGTGGC
0,57

ID
316

656

#316

SEQ
COMP ID
5′-CTGGCCACAGGGTCCACT-3′
2254
2271
SEQ ID
AGTGGACCCTGTGGCCAG
0,51

ID
317

657

#317

SEQ
COMP ID
5′-CACCTGGCCACAGGGTCC-3′
2257
2274
SEQ ID
GGACCCTGTGGCCAGGTG
0,73

ID
318

658

#318

SEQ
COMP ID
5′-AAGCACCTGGCCACAGGG-3′
2260
2277
SEQ ID
CCCTGTGGCCAGGTGCTT
0,43

ID
319

659

#319

SEQ
COMP ID
5′-GAAAAGCACCTGGCCACA-3′
2263
2280
SEQ ID
TGTGGCCAGGTGCTTTTC
0,33

ID
320

660

#320

SEQ
COMP ID
5′-AGGGAAAAGCACCTGGCC-3′
2266
2283
SEQ ID
GGCCAGGTGCTTTTCCCT
0,16

ID
321

661

#321

SEQ
COMP ID
5′-GATAGGGAAAAGCACCTG-3′
2269
2286
SEQ ID
CAGGTGCTTTTCCCTATC
0,65

ID
322

662

#322

SEQ
COMP ID
5′-GTGGATAGGGAAAAGCAC-3′
2272
2289
SEQ ID
GTGCTTTTCCCTATCCAC
0,54

ID
323

663

#323

SEQ
COMP ID
5′-CCTGTGGATAGGGAAAAG-3′
2275
2292
SEQ ID
CTTTTCCCTATCCACAGG
0,63

ID
324

664

#324

SEQ
COMP ID
5′-ACCCCTGTGGATAGGGAA-3′
2278
2295
SEQ ID
TTCCCTATCCACAGGGGT
0,29

ID
325

665

#325

SEQ
COMP ID
5′-AACACCCCTGTGGATAGG-3′
2281
2298
SEQ ID
CCTATCCACAGGGGTGTT
0,62

ID
326

666

#326

SEQ
COMP ID
5′-ACAAACACCCCTGTGGAT-3′
2284
2301
SEQ ID
ATCCACAGGGGTGTTTGT
1,08

ID
327

667

#327

SEQ
COMP ID
5′-CACACAAACACCCCTGTG-3′
2287
2304
SEQ ID
CACAGGGGTGTTTGTGTG
0,81

ID
328

668

#328

SEQ
COMP ID
5′-ACACACACAAACACCCCT-3′
2290
2307
SEQ ID
AGGGGTGTTTGTGTGTGT
0,88

ID
329

669

#329

SEQ
COMP ID
5′-CGCACACACACAAACACC-3′
2293
2310
SEQ ID
GGTGTTTGTGTGTGTGCG
0,60

ID
330

670

#330

SEQ
COMP ID
5′-ACGCGCACACACACAAAC-3′
2296
2313
SEQ ID
GTTTGTGTGTGTGCGCGT
0,68

ID
331

671

#331

SEQ
COMP ID
5′-CACACGCGCACACACACA-3′
2299
2316
SEQ ID
TGTGTGTGTGCGCGTGTG
0,51

ID
332

672

#332

SEQ
COMP ID
5′-ACGCACACGCGCACACAC-3′
2302
2319
SEQ ID
GTGTGTGCGCGTGTGCGT
0,25

ID
333

673

#333

SEQ
COMP ID
5′-GAAACGCACACGCGCACA-3′
2305
2322
SEQ ID
TGTGCGCGTGTGCGTTTC
0,66

ID
334

674

#334

SEQ
COMP ID
5′-ATTGAAACGCACACGCGC-3′
2308
2325
SEQ ID
GCGCGTGTGCGTTTCAAT
0,82

ID
335

675

#335

SEQ
COMP ID
5′-TTTATTGAAACGCACACG-3′
2311
2328
SEQ ID
CGTGTGCGTTTCAATAAA
0,76

ID
336

676

#336

SEQ
COMP ID
5′-AACTTTATTGAAACGCAC-3′
2314
2331
SEQ ID
GTGCGTTTCAATAAAGTT
0,73

ID
337

677

#337

SEQ
COMP ID
5′-ACAAACTTTATTGAAACG-3′
2317
2334
SEQ ID
CGTTTCAATAAAGTTTGT
0,84

ID
338

678

#338

SEQ
COMP ID
5′-TGTACAAACTTTATTGAA-3′
2320
2337
SEQ ID
TTCAATAAAGTTTGTACA
0,98

ID
339

679

#339

SEQ
COMP ID
5′-AAGTGTACAAACTTTATT-3′
2323
2340
SEQ ID
AATAAAGTTTGTACACTT
0,87

ID
340

680

#340

SEQ
COMP ID
5′-AGAAAGTGTACAAACTTT-3′
2326
2343
SEQ ID
AAAGTTTGTACACTTTCT
0,72

ID
341

681

#341

SEQ
COMP ID
5′-TTAAGAAAGTGTACAAAC-3′
2329
2346
SEQ ID
GTTTGTACACTTTCTTAA
0,87

ID
342

682

#342

Example 7: 16-Mer Oligos Targeting the 5′ UTR

16-mer Oligos targeting 5′ UTR uORF region (SEQ ID Nos 95-136) were selected, prepared and profiled for effects on Progranulin protein expression.

H4 neuroglioma cells were seeded in 96 well plates 5000 pr well, and treated with 10 μM final concentration of compounds for 5 days in 200 μL medium.

Microglia cells were chosen for analysis because these cells produce high levels of progranulin. Reduction of progranulin in microglia cells alone is sufficient to effect inflammation, lysosomal dysfunction, and hyperproliferation in a cell-autonomous manner. Therefore, targeting microglial dysfunction caused by progranulin insufficiency represents a potential therapeutic strategy to manage neurodegeneration in Frontotemporal dementia. To study effects on Progranulin in cellular systems, H4 cells (ATCC HTB-148) a commercial available glial cell line derived from a cancer patient have been used for identifying oligonucleotides capable of increasing progranulin production.

To further use Microglia that exhibit functional characteristics similar to human microglia, including phagocytosis and cytokine-mediated inflammatory responses, and express relevant microglial markers, hiPSC derived microglia iCell® Microglia from FujiFilm Cellular Dynamics Inc. (Cat. no R1131) have been used for investigating effects of selected oligonucleotides on progranulin production.

Progranulin expression levels were evaluated in media after dilution 1:8 by ELISA from Abcam (ab252364). Compound #105, #106, #110, #113 and #114 induced progranulin secretion more than 150% compared to PBS as shown in FIG. 1.

Compounds #105, #106, #110 and #114 localise on the 5′ UTR of Proganulin transcript, targeting the uORF region as shown in FIG. 2.

H4 cells were seeded in 96 well plates 5000 pr well, and treated with 10 μM final concentration of compounds for 5 days in 200 μL medium. Progranulin expression levels were evaluated in cell lysate (RIPA lysis and extraction buffer from Pierce cat. No. 89900) using the WES platform (ProteinSimple) and GRN antibody Invitrogen PA5-27275 diluted 1:25 and HPRT1 antibody ab109021 (Abcam) diluted 1:50. GRN expression was normalized to endogenous housekeeping protein HPRT1.

Compounds #106, #110, and #114 induced Progranulin in cell lysate compared to PBS as shown in FIGS. 3 and 4.

Example 8: Compound #106

hiPSC derived microglia (iCell Microglia Kit, 01279, Cat. no R1131) were seeded in 48 well plates with 100000 pr well in 500 μL, and were treated with varying concentrations of Compound #106 for 5 days.

Progranulin expression levels were evaluated in media after dilution 1:8 by ELISA from Abcam (ab252364).

Compound #106 (n=3) dose-dependently induced Progranulin secretion compared to PBS as shown in FIG. 5.

Example 9: 18-Mer Oligos Targeting 5′ UTR

18-mer Oligos targeting 5′ UTR uORF region (SEQ ID NOs: 207-245) were selected, prepared and profiled for effects on Progranulin protein expression.

H4 neuroglioma cells were seeded in 96 well plates 5000 pr well and treated with 10 μM final concentration of compounds for 5 days in 200 μL medium. Progranulin expression levels were evaluated in media after dilution 1:8 by ELISA from Abcam (ab252364).

Compound #231 and #241 induced Progranulin secretion compared to PBS as shown in FIG. 6.

Example 10: Compound #106

The structure of Compound ID #106 (SEQ ID NO 106) inducing upregulation of Progranulin in both H4 cells and hiPSC derived Microglia cells, is shown in FIG. 7.

Example 11: Full 2′MOE and 2′oMe Modified Versions of SEQ ID NO: 106

SEQ ID NO: 106 (TGGCCAGGGATCAGGG) was tested as both a full 2′MOE modified oligo (Compound #106 full 2′MOE) and a full 2′oMe modified oligo (Compound #106 full 2′oMe).

H4 neuroglioma cells seeded in 96 well plates 5000 pr well were treated with 10 μM final concentration of compounds for 5 days in 200 μL medium. Progranulin expression levels were evaluated in media after dilution 1:8 by ELISA from Abcam (ab252364). Compound #106 and Compound #106 full 2′MOE and Compound #106 full 2′oMe induced a ˜2-fold increase in progranulin secretion to the media compared to PBS.

Example 12: Gene Transcript Regulation by Compound #106, Compound #106 Full 2′MOE and Compound #106 Full 2′oMe

To understand the number of gene transcripts regulated by compound #106, Compound #106 full 2′MOE and Compound #106 full 2′oMe, H4 neuroglioma cells seeded in 48 well plates 15000 per well were treated with 10 μM final concentration of compounds for 5 days in 500 μL medium. mRNA was isolated using the MagNAPure 96 system (Roche) according to manufacturer's protocol. The purified mRNA were sent for gene expression array analysis at Eurofins Genomics, using Clariom™ S Arrays (ThermoFisher Scientific). Expression analysis was conducted using the Qlucore Omics Explorer software, using a two-group comparison and by adjusting the FDR<0.1. The number of genes regulated more than 2-fold either up and down compared to PBS were identified. Compound #106 showed 1207 genes regulated more than 2-fold, Compound #106 full 2′oMe showed 782 genes regulated more than 2-fold, whereas Compound #106 full 2′MOE only showed 43 transcripts regulated. FIG. 9 shows that Compound #106 full 2′MOE has less off-targets compared to compound #106 and Compound #106 full 2′oMe.

The genes regulated more than 2-fold with a FDR<0.1 are shown below.

Genes regulated more than 2-fold with a FDR<0.1 following treatment with Compound #106: AATF, ABCA1, ABCC2, ABCC3, ABCG1, ABLIM3, ACAT2, ACKR3, ACSL5, ACSS3, ACTA2, ACVR1B, ADAM9, ADAMTS16, ADAMTS19, ADAMTS3, ADAMTSL4, ADGRA3, ADGRB3, ADI1, ADRBK1, ADRM1, ADSL, AFAP1, AGT, AHCY, AHI1, AHNAK2, AHR, AJAP1, AKAP6, ALCAM, ALDH1L2, ALDH3A1, ALDOA, ALDOC, ALG8, ALKBHS, ALPK2, ALYREF, AMMECR1, AMMECR1L, AMPD2, AMTN, ANGPT1, ANK3, ANKRD18A, ANKRD44, ANLN, ANO7, ANPEP, ANTXR2, ANXA1, AOAH, APCDD1, APEX1, APH1A, APOBEC3B, APOL2, APOL3, APRT, AQP1, AQP3, ARAF, ARCN1, ARHGAP11B, ARHGAP35, ARHGAP8, ARHGEF2, ARL4A, ARMC6, ARPC4, ARPC4-TTLL3, ARRDC3, ARRDC4, ARSG, ASNA1, ASNS, ASPM, ASS1, ATAD2, ATN1, ATP6AP1L, ATP6V0A1, ATP8B3, ATXN2, ATXN2L, AVEN, B4GALT5, BCAM, BCL6, BDNF, BEX1, BHLHE40, BIRC5, BLID, BLM, BMP5, BNC2, BNIP3, BNIP3L, BSG, BTAF1, BUB1B, C10orf10, C10orf107, C12orf76, C17orf89, C1RL, C1orf174, C1orf21, C1orf52, C1orf53, C20orf24, C7orf26, C7orf73, C8orf4, C8orf48, C8orf58, CA12, CA5B, CA9, CACNG4, CACYBP, CALCOCO1, CALR, CAMK4, CAPNS1, CAPZB, CASC5, CASK, CBLB, CCBL1, CCDC102B, CCDC150, CCDC163P, CCDC34, CCNA2, CCNB1, CCNB2, CCND1, CCNE2, CCPG1, CCT2, CD151, CD24, CD55, CD96, CD99, CD99, CDC20, CDC42SE1, CDC45, CDC6, CDCA5, CDCA8, CDH6, CDH8, CDK1, CDKN1A, CDKN3, CDT1, CENPA, CENPF, CENPH, CENPI, CENPM, CENPN, CENPU, CENPW, CEP128, CEP19, CEP55, CEP78, CFC1, CFH, CFI, CFL1, CHAC1, CHAC2, CHAF1B, CHMP1B, CHP1, CHST15, CKAP2, CKS2, CLEC2D, CLIC4, CLIP4, CLK2, CLMN, CLSPN, CLSTN2, CLTA, CLTB, CMTM7, CNTNAP1, CNTNAP3, CNTNAP3B, CNTNAP3B, CNTNAP3P2, COASY, COBLL1, COG7, COL1A1, COL21A1, COL3A1, COL5A2, COLEC12, COMMD3-BMI1, COPRS, COPZ1, CORIN, CORO2B, COX2, COX5A, CP, CPA4, CPD, CPSF3, CRISPLD1, CSF1, CSGALNACT1, CTBP2, CTBS, CTH, CTNND1, CTSB, CTSC, CTSL, CTSO, CUL7, CXADR, CXCL14, CXCL8, CYB5D2, CYTL1, DACT1, DBI, DBN1, DCTPP1, DDIT4, DDR2, DDX39A, DDX46, DECR1, DEDD, DEPDC1, DEPTOR, DGKD, DGKD, DGKD, DGKD, DGKD, DGKD, DHCR24, DHFR, DHRS3, DHX15, DHX9, DLGAP5, DLX1, DMKN, DOCK10, DPT, DPYD, DPYSL2, DPYSL3, DPYSL5, DSEL, DSN1, DSTN, DTNBP1, DUSP6, E2F8, EBI3, EBP, EDC4, EDEM1, EDIL3, EEF1B2, EEPD1, EFEMP2, EFTUD1, EGLN3, EGR1, EID1, EIF5, EIF5A, EIF6, ELAVL2, EMP1, ENC1, ENCASE, ENO2, ENPP1, ENPP2, ENTPD4, EPAS1, EPHX1, EPT1, ERGIC1, ERH, ERN1, ERO1A, ERRFI1, ETV1, ETV5, EXO1, EXT1, EXT1, EYA4, FAM101B, FAM111A, FAM111B, FAM114A1, FAM127B, FAM13A, FAM13C, FAM155A, FAM155A, FAM155A, FAM160A2, FAM161A, FAM162A, FAM200B, FAM20B, FAM214B, FAM219A, FAM234A, FAM46A, FAM83D, FANCA, FANCD2, FANC1, FBL, FBN1, FBXO32, FBXO36, FBXO44, FBXO7, FCHSD1, FDPS, FDX1L, FEM1C, FEM1C, FEN1, FGF7, FH, FIBIN, FJX1, FKBP10, FKBP1A, FKBP1A-SDCBP2, FKBP9, FLOT1, FLOT2, FLRT2, FN1, FNBP4, FOSL1, FOSL2, FOXF1, FOXF2, FOXK1, FOXM1, FRMD4B, FSCN1, FSTL1, FSTL4, FTSJ2, FUCA1, FUNDC2, FURIN, FUS, FUT11, FXYD5, FYCO1, GABRE, GALNT1, GALNT13, GANAB, GAR1, GATAD1, GBA, GBE1, GCLC, GCSH, GDI1, GFPT1, GFRA1, GFRA2, GINS1, GINS2, GLCCI1, GLI3, GLIPR2, GLIS3, GLRX2, GLT8D2, GLUL, CML, GMNN, GNAI1, GPAA1, GPATCH2L, GPATCH4, GPI, GPNMB, GPR137C, GPR34, GPRC5B, GPT2, GRAMD1A, GRINA, GRM8, GRWD1, GTF3A, GTPBP6, GTPBP6, H2AFV, H2AFX, H2AFY2, H6PD, HDAC9, HELLS, HGF, HIBCH, HILPDA, HIST1H1B, HIST1H1C, HIST1H1D, HIST1H1E, HIST1H2AB, HIST1H2AG, HIST1H2AH, HIST1H2A1, HIST1H2AJ, HIST1H2AL, HIST1H2AM, HIST1H2BF, HIST1H2BG, HIST1H2BH, HIST1H2B1, HIST1H2BJ, HIST1H2BK, HIST1H2BL, HIST1H2BO, HIST1H3B, HIST1H3D, HIST1H3F, HIST1H3G, HIST1H3H, HIST1H4B, HIST1H4C, HIST1H4D, HIST1H4H, HIST1H41, HIST2H2AA3, HIST2H2AA4, HIST2H2AB, HIST2H2AC, HIST2H2BE, HIST2H2BF, HIST2H3A, HIST2H3A, HIST2H3D, HIST2H4A, HIST2H4B, HIST3H2A, HIST3H2BB, HJURP, HK2, HLTF, HMGB3, HMGCS1, HMGCS2, HNRNPM, HOXA13, HOXA3, HOXB3, HPCAL1, HS6ST2, HSD17B13, HSF4, HSP90AA1, HSPA13, HSPB3, HSPH1, HTATSF1, HTR7, ID2, ID3, IDH2, ID11, IDO1, IER3, IFI16, IFI44L, IFITM1, IFITM2, IFITM3, IFNGR2, IGF2, IGF2BP3, IGFBP3, IGFBP5, IK, IL13RA1, IL13RA2, IL1R1, IL1RAP, IL20RB, IL32, IL6, INAFM1, INHBB, INSIG2, IRF9, ISY1, ITFG2, ITGA11, ITGA2, ITGA3, ITGA4, ITGA5, ITGA6, ITGA8, ITGAX, ITGB3, ITGB5, ITGB6, ITGBL1, ITM2C, ITPKB, JAK2, JAK2, JUN, KAZALD1, KCNQ3, KCTD11, KDM4C, KDM5C, KEAP1, KIAA0101, KIAA1456, KIF11, KIF14, KIF15, KIF15, KIF15, KIF15, KIF15, KIF18A, KIF20A, KIF22, KIF23, KIF2C, KIF4A, KIFC1, KLF10, KLF9, KLHL4, KNSTRN, KNTC1, KPNA2, KPTN, KRT17, KRT81, KYNU, LACTB, LAMA1, LAMB1, LAMTOR4, LANCL2, LBH, LEF1, LEFTY2, LHX8, LIF, LIFR, LIMCH1, LINC00473, LINGO2, LMAN1, LMBR1L, LMNB1, LMNB2, LMNTD2, LOC100130880, LOX, LPAR6, LPCAT1, LPXN, LRIG3, LRP1, LRRC1, LRRC15, LRRC17, LRRC23, LRRC8C, LRRTM4, LRRTM4, LSAMP, LSG1, LSM3, LSM5, LUZP1, LY6E, LYPD6B, MAGEA1, MAP1LC3C, MAP2K6, MAP3K7CL, MAP9, MAPK14, MAPK1IP1L, MAPK3, MAPRE3, MARS, MASP1, MATN2, MBOAT7, MCAT, MCFD2, MCM2, MCM3, MCM4, MCM5, MCM6, MCM7, MCM8, MCOLN1, MCTP2, MDH1B, MECOM, MEF2A, MEIS2, MELK, METTL15, MFAP3L, MFSD1, MFSD10, MGAT5, MGST3, MILR1, MIR99AHG, MK167, MMAB, MMD, MMP13, MMP3, MNS1, MOCOS, MOCS2, MOGS, MORF4L2, MOSPD2, MPI, MPP7, MPPED2, MPRIP, MRPL3, MRPL51, MRPL57, MRPS11, MSANTD2, MSH2, MT1B, MT1G, MT1IP, MT1L, MT1X, MT2A, MTCH2, MTERF3, MTHFD1, MTIF2, MTPAP, MX1, MYADM, MYBL2, MYLK, MYO6, MYO6, NAGK, NALCN, NAMPT, NANOS1, NAP1L1, NAPA, NASP, NCAM1, NCAPD2, NCAPG, NCAPH, NCK1, NCKAP5, NCL, NCOA4, NCOA7, ND4L, NDC80, NDNF, NDRG1, NDUFA4L2, NDUFS6, NDUFS8, NEIL3, NETO2, NEU1, NEXN, NFAT5, NFE2, NFE2L1, NFKB2, NFKBIA, NFYB, NHEJ1, NHP2, NMI, NOL3, NPIPA1, NPIPA5, NPIPA7, NPIPA7, NPIPA8, NR2C1, NR2F1, NR4A1, NSDHL, NSMAF, NSUN4, NUAK1, NUSAP1, NXPH4, NYAP2, OAS1, OAS2, OASL, OCIAD2, ODC1, OGN, OGT, OLA1, OLFML2B, OLFML3, OR8B12, ORAI3, ORC1, ORC6, OSBPL3, OSGEP, OSMR, OXCT1, P4HA1, P4HA2, PABPC4, PAFAH1B3, PAK1IP1, PAN2, PAQR6, PARD3B, PARM1, PARP14, PCDH10, PCF11, PCMTD1, PCNA, PCNX, PCP4, PCYOX1L, PDE10A, PDE4B, PDE5A, PDGFD, PDGFRA, PDIA4, PDK1, PDLIM5, PELI1, PELO, PEPD, PFKFB4, PFKP, PGAM1, PGK1, PHF19, PHLDA1, PIDD1, PIF1, PIK3R3, PITPNM1, PITX1, PLA2G6, PLACE, PLAGL1, PLAT, PLAU, PLD1, PLD1, PLEKHA2, PLEKHG1, PLEKHS1, PLIN2, PLK4, PLN, PLOD1, PLOD2, PLOD3, PLPP3, PLPP4, PLSCR1, PLXDC2, PLXNC1, PMEPA1, PMM2, PNPLA2, PNPLA6, PNRC1, PODXL, POLQ, POLR1E, POLR2J4, POLR3D, POMT1, PON2, POSTN, PPARGC1A, PPIL1, PPM1B, PPP1R37, PPP1R7, PPP1R8, PPP3CA, PQBP1, PRADC1, PRC1, PRH1, PRIM1, PRKAA2, PRKAB2, PRKAR1A, PRKDC, PRKG1, PROCR, PROZ, PRR4, PRRC2B, PRRT1, PRUNE2, PSAT1, PSD3, PSMA2, PSMB1, PSMD1, PSMD2, PSMD3, PSMD9, PSMG1, PSMG2, PTAR1, PTCHD1, PTGES, PTGES3L-AARSD1, PTGR2, PTGS2, PTPMT1, PTPN13, PTPRG, PTPRM, PTPRN2, PUS7L, PVRL2, QRICH2, RAB27A, RAB33B, RAB7B, RABEP2, RABGGTA, RAD51, RAD51AP1, RAD51C, RALGAPA2, RALGPS2, RANBP3L, RASA4, RASL11A, RBL1, RBL2, RBM3, RBM8A, RBPMS, RCN3, REC8, RECQL4, RELA, REPS1, RFC4, RFPL4A, RGL2, RGS10, RGS18, RGS2, RMI2, RNF144A, RNF145, RNF213, RNF24, RNPEP, RORA, RP11-307P5.1, RPP21, RPP30, RPP40, RPS26, RPS26, RPS6KA3, RRAGC, RRAS, RRBP1, RRM1, RRM2, RTKN2, RTN3, RUNX2, RWDD1, S100A10, SAFB2, SAMD15, SAMD5, SAMD8, SAT1, SATB2, SBNO2, SCAMP3, SCARA3, SCN9A, SCOC, SCRIB, SDC4, SEC14L2, SEC23B, SECISBP2L, SEL1L3, SEMA3C, SEMA4B, SEMA6D, SERHL2, SERINC5, SERPINA3, SETD5, SF3B1, SFR1, SFRP4, SGIP1, SGK1, SGOL2, SGSH, SH3BGRL3, SH3BP2, SHB, SHC1, SHC4, SHCBP1, SHISA5, SHMT1, SIDT2, SIGMAR1, SKA2, SLC14A1, SLC16A1, SLC16A1, SLC16A3, SLC16A4, SLC16A6, SLC1A3, SLC1A5, SLC20A1, SLC25A19, SLC25A36, SLC25A37, SLC26A11, SLC29A1, SLC29A4, SLC2A1, SLC2A14, SLC2A3, SLC35F5, SLC37A3, SLC43A2, SLC4A4, SLC6A6, SLC7A5, SLCO4A1, SLFN5, SLIT2, SLITRK2, SLPI, SMAD7, SMAD9, SMAGP, SMC3, SMIM3, SMOX, SMPD1, SMPDL3A, SNAI1, SNAPC3, SNED1, SNRNP25, SNRPF, SNX2, SNX33, SOBP, SOCS4, SOCS5, SORT1, SOST, SPC24, SPC25, SPDL1, SPOCD1, SPON2, SPP1, SPRY1, SPRY3, SPRY3, SPRY4, SQLE, SRM, SRPX2, SRRT, SSBP2, ST8SIA4, STAG3L4, STC1, STC2, STEAP1B, STEAP2, STEAP3, STIL, STK11IP, STRA6, STXBP5L, SURF4, SURF4, SURF4, SURF4, SUV39H1, SVIP, SYNC, SYNJ2, SYT14, SYTL2, TACC3, TADA3, TAF9, TAF9B, TAGLN2, TANGO6, TAPBP, TAS2R31, TBC1D1, TBC1D28, TBC1D31, TBL1X, TBXAS1, TCEAL2, TCEAL4, TCF19, TCHP, TCP1, TDO2, TEX264, TFAP2A, TFAP2C, TFPI, TFRC, TGFA, TGFB2, THTPA, TIMELESS, TIMM10, TIMP1, TIMP3, TIPARP, TM2D2, TM4SF1, TM9SF4, TMED4, TMED7-TICAM2, TMEM100, TMEM160, TMEM182, TMEM2, TMEM2, TMEM230, TMEM30A, TMEM39A, TMEM70, TMEM97, TMEM98, TMEM99, TMPO, TMSB15A, TMUB1, TNFRSF10B, TNFRSF1A, TNFRSF9, TNFSF10, TOE1, TOMM34, TOP2A, TOR3A, TP63, TPBG, TPCN1, TPM1, TPMT, TPX2, TRAPPC2L, TRAPPC4, TRAPPC5, TRIB2, TRIB3, TRIM22, TRIM25, TRIM36, TRIMS, TRIP10, TRIP13, TRIT1, TRMO, TROAP, TSPAN9, TSR2, TSR3, TTC25, TTC37, TTLL12, TUBG2, TVP23C, TWISTNB, TXN, TXNIP, TYMS, U2AF1, UBE2C, UBR7, UGGT2, UHRF1, UMPS, UNC93B1, UNG, USP3, VAT1, VCAM1, VCAN, VGF, VOPP1, VPS11, VRK1, VWA5A, WARS, WDR27, WDR34, WDR60, WDR62, WDR76, WDR90, WNT2B, WNT5B, WSB1, XBP1, XRCC2, XRCC3, XRCC6BP1, YEATS4, YIF1A, YY1AP1, ZBED6, ZBTB25, ZC4H2, ZDHHC15, ZDHHC4, ZNF160, ZNF326, ZNF358, ZNF382, ZNF395, ZNF414, ZNF511, ZNF512B, ZNF521, ZNF529-AS1, ZNF532, ZNF570, ZNF667, ZNF682, ZNF692, ZNF777, ZNF785, ZNF830, ZNF92, ZWILCH and ZWINT.

Genes regulated more than 2-fold with a FDR<0.1 following treatment with Compound #106 full 2′oMe: AARS, ABCA1, ABLIM1, ACAT2, ACSL5, ADAM9, ADAMTS16, ADAMTS19, ADAMTSL4, ADGRA2, ADRBK1, ADRM1, ADSSL1, AGPS, AGRN, AGT, AHNAK, AHNAK2, AHR, AJAP1, AK7, AKAP12, AKAP6, AKR1C2, AKR1C3, ALCAM, ALDH1L2, ALDH3A1, ALDOC, ALPK2, ALYREF, AMTN, ANK3, ANKRD44, ANPEP, ANTXR2, AOAH, AP4S1, APCDD1, AQP1, ARHGAP11B, ARHGDIB, ARHGEF2, ARL15, ARMC6, ARRDC3, ARRDC4, ARSG, ASPN, ATAD2, ATHL1, ATP13A2, ATP6AP1L, ATP6V1C1, ATXN1, AURKB, BANF1, BCAR3, BCAT1, BCL6, BCO1, BDNF, BEX1, BLID, BMP5, BNC2, BNIP3, BSG, BST2, BTAF1, BTG2, BTG3, BUB1, BUB1B, C10orf107, C14orf1, C14orf132, C1QTNF3, C3orf14, C3orf58, C4A, C4B, C8orf4, C9orf43, C9orf50, CA12, CA9, CACNG4, CALCB, CAMK4, CARS, CASK, CASP4, CBFA2T3, CCDC102B, CCDC34, CCNA2, CCPG1, CD24, CD55, CD82, CD96, CDC45, CDC6, CDCA3, CDCA5, CDCA8, CDH6, CDK1, CEBPG, CENPF, CENPI, CENPM, CENPN, CENPU, CEP128, CFH, CFI, CHAC1, CHEK1, CHL1, CHMP1B, CHRNA1, CHRNA9, CHST15, CLDND1, CLEC2B, CLIC2, CLIC5, CLMN, CLSTN2, CMKLR1, CMTM3, CNPPD1, CNTNAP1, CNTNAP3, CNTNAP3B, CNTNAP3B, CNTNAP3P2, COBLL1, COL1A1, COL3A1, COL5A2, COLEC12, CORIN, CP, CPA4, CSF1, CSGALNACT1, CSGALNACT2, CSNK1E, CTBP1, CTBS, CTH, CTNS, CTSC, CXADR, CXCL14, CXCL3, CXCL8, CYP51A1, CYTH3, DACT1, DACT1, DBI, DBN1, DDIT4, DDX39A, DDX58, DDX60, DECR1, DEPTOR, DET1, DGKD, DGKD, DGKD, DGKD, DGKD, DHCR24, DHCR7, DHFR, DHFR, DHRS3, DHX58, DLG3, DLGAP5, DLX1, DNAH5, DNAJB1, DOCK10, DPT, DPYSL3, DSEL, DSN1, DUSP10, DUSP6, EBP, EEPD1, EFEMP2, EFTUD1, EGLN3, EID1, EIF2AK2, ELAVL2, EMP1, ENC1, ENGASE, ENO1, ENO2, ENPP2, ENTPD4, EPAS1, ERICH1, ERO1A, ERRFI1, ETV1, EXO1, EXT1, EXT1, F3, FAM111A, FAM111B, FAM118B, FAM13A, FAM13C, FAM155A, FAM155A, FAM161A, FAM162A, FAM198B, FAM20C, FAM46A, FAM83D, FANCI, FAP, FAS, FBLN5, FBN1, FBXO32, FGF7, FJX1, FLOT1, FN1, FOXF2, FOXM1, FSTL1, FSTL4, FUT11, GABRE, GADD45A, GATAD1, GBE1, GCLC, GDF15, GDI1, GFRA1, GINS1, GINS2, GLRX, GLT8D2, GLUL, GMFG, GNAI1, GNPDA1, GPC4, GPCPD1, GPI, GPNMB, GPRC5B, GPS2, GPT2, GPX3, GRIP1, H2AFV, H2AFX, HACE1, HDAC9, HDLBP, HGF, HHAT, HIPK2, HIST1H1B, HIST1H1C, HIST1H1D, HIST1H1E, HIST1H2AG, HIST1H2AH, HIST1H2A1, HIST1H2AJ, HIST1H2AL, HIST1H2AM, HIST1H2BF, HIST1H2BH, HIST1H2BI, HIST1H2BJ, HIST1H2BK, HIST1H2BL, HIST1H3B, HIST1H3F, HIST1H3G, HIST1H3H, HIST1H4B, HIST1H4C, HIST1H4H, HIST2H2AA3, HIST2H2AA4, HIST2H2AB, HIST2H2AC, HIST2H2BE, HIST2H2BF, HIST2H3A, HIST2H3A, HIST2H3D, HIST2H4A, HIST2H4B, HIST3H2BB, HLA-DRA, HMCN1, HMGB3, HMGCR, HMGCS1, HMGN2, HNRNPM, HOXA3, HPCAL1, HS6ST2, HSD17B10, HSD17B13, HSF4, HSP90B1, HSPB3, HTR7, ID3, ID11, IDO1, IER3, IF116, IF127, IF144, IF144L, IF16, IFITM1, IFITM2, IFITM3, IGF1, IGFBP3, IGFBP5, IL13RA1, IL13RA2, IL1R1, IL20RB, IL6, IL7R, ILF2, INAFM1, INHBA, INHBB, INSIG1, INSIG2, IRF9, ITGA11, ITGA2, ITGA5, ITGA6, ITGA8, ITGAX, ITGB6, ITGBL1, ITPKB, JAK2, JUN, KBTBD11, KCNH1, KCNQ3, KIAA0101, KIAA1456, KIF11, KIF15, KIF15, KIF15, KIF20A, KIF22, KIF23, KIF26B, KIF2C, KIF4A, KIFC1, KIRREL3, KPNA2, KRT17, KRTAP9-3, KYNU, LACTB, LAMB1, LBH, LEF1, LEFTY1, LEMD1, LEPR, LFNG, LGR4, LIF, LIMCH1, LINC00473, LINC00663, LINC01565, LINGO2, LITAF, LMAN1, LMNB1, LMNB2, LOX, LPAR6, LPCAT1, LRIG3, LRRC15, LRRC23, LRRN1, LRRTM4, LSAMP, LSS, LST1, LXN, LY6E, LY6E, LYPD6B, MAP1LC3C, MAP2K6, MAP3K5, MAP3K7CL, MASP1, MB21D2, MCM2, MCM3, MCM4, MCM5, MCOLN1, MCTP2, MECOM, MEIS2, MELK, MERTK, MET, MFAP2, MFAP3L, MFAP4, MFSD10, MGLL, MGP, MILR1, MIR99AHG, MK167, MMD, MMP13, MOCOS, MPI, MPP7, MPPED2, MSC, MSH2, MT1X, MTFR2, MTHFD1, MTIF2, MX1, MX2, MYBL2, MYLK, MYO5B, MYO6, NAMPT, NANOS1, NBL1, NBN, NCAM1, NCAPD2, NCAPG, NCKAP1, NCOA7, NDC80, NDNF, NDOR1, NDUFA4L2, NES, NEXN, NFE2, NFKBIA, NKAP, NNT, NOL3, NPAS2, NPIPA1, NPIPA5, NPIPA7, NPIPA8, NQO1, NR2F1, NREP, NTM, NUAK1, NUCB2, NUDT22, NUSAP1, NXPH4, NYAP2, OAS1, OAS2, OBFC1, OLFM1, OLFML2A, OLFML2B, OLFML3, OR5H1, OSBPL3, OSGEP, OSMR, OXCT1, P2RX7, P4HA1, PABPC1, PABPC1L2A, PADI3, PADI3, PAN2, PARM1, PARP1, PARP14, PARP9, PAX9, PCDH10, PCNA, PCNX, PCP4, PDE10A, PDE5A, PDGFD, PDGFRA, PDIK1L, PDK1, PDK2, PDLIM5, PEPD, PFKFB4, PFKP, PGK1, PHLDA1, PIDD1, PIK3R3, PITX1, PKD1, PLACE, PLAT, PLAU, PLD1, PLD1, PLIN2, PLK1, PLK4, PLOD1, PLPP3, PLPP4, PLSCR1, PLXDC2, PMEPA1, PNPLA3, POFUT2, POLD2, POLR1E, POLR2J4, POSTN, POU6F1, PPARG, PPARGC1A, PPP1CC, PRC1, PREX2, PRICKLE1, PRIM1, PRKAA2, PRKD1, PROCR, PRR11, PRSS12, PRUNE2, PSD3, PSG4, PTCH1, PTCHD1, PTGES, PTGS2, PTPN13, PTPRM, PVRL2, PXDC1, PYROXD1, RAB27A, RAB43, RACGAP1, RAD54L, RALGAPA2, RANBP3L, RAP2B, RASL11A, RASL11B, RBL2, RBM3, RBPMS, RCN3, REC8, RELB, RGS10, RGS18, RGS2, RHOJ, RNF145, RNF217, RNFT2, RORA, RPS6KA3, RRAGC, RRM1, RTKN2, RUNX2, SAMD15, SAMD8, SAT1, SATB2, SBNO2, SC5D, SDC4, SDR42E1, SECISBP2L, SEL1L3, SEMA4B, SERINC5, SERPINB1, SERPINE2, SERTAD4, SESN3, SFRP4, SGIP1, SGK1, SGOL1, SGSH, SHC1, SHC4, SHCBP1, SHISA5, SHMT1, SIDT2, SIX1, SLC14A1, SLC16A3, SLC16A4, SLC16A6, SLC1A3, SLC20A1, SLC25A37, SLC29A1, SLC29A4, SLC2A14, SLC2A3, SLC39A8, SLC44A4, SLC4A4, SLC50A1, SLC7A5, SLC9A3R2, SLCO1C1, SLCO4A1, SLFN5, SLIT2, SLITRK2, SLPI, SMAD9, SNAI1, SNAP25, SNAPC1, SNX8, SORBS2, SORT1, SPAG4, SPC24, SPC25, SPDL1, SPECC1, SPOCD1, SPP1, SPRY1, SSBP2, ST8SIA4, STARD4, STAT1, STC1, STC2, STEAP2, STEAP3, STMN1, SULT1E1, SYNC, SYNGR1, SYNM, SYT14, TACC3, TAF9B, TBC1D2, TBC1D3L, TBL1X, TDO2, TET3, TFAP2C, TFB1M, TFPI, TFRC, TGFB2, TIMELESS, TIMP1, TIMP3, TIPARP, TK1, TLR3, TM4SF1, TMCO4, TMEM100, TMEM140, TMEM189, TMEM19, TMEM2, TMEM255A, TMEM257, TMEM97, TNC, TNFRSF10B, TNFRSF9, TNFSF10, TOB1, TOP2A, TP63, TPBG, TPM1, TPM2, TPX2, TRAPPC2L, TRIB2, TRIB3, TRIM36, TRIM49C, TSPAN2, TSPAN9, TUBA1A, TVP23C, TXK, TXNIP, TYMS, UAP1L1, UBR7, UHRF1, VASH2, VCAM1, VCAN, VEGFA, VGLL2, VWA5A, WARS, WDR60, WDR62, WDR76, WFDC3, WFS1, WNT2B, WSB1, XBP1, XRCC2, YARS, YIF1A, ZBTB25, ZFP36L2, ZNF395, ZNF521, ZNF667, ZNF804A and ZNF814.

Genes regulated more than 2-fold with a FDR<0.1 following treatment with Compound #106 full 2′MOE: ACAT2, ADI1, ARRDC4, CCPG1, CDCA5, COL3A1, CP, CXCL8, EFEMP2, ENC1, FANCD2, FBN1, HIST1H1B, HIST1H2AG, HIST1H2A1, HIST1H2AL, HIST1H2BA, HIST1H3B, HIST2H2AA4, HIST2H2BF, HIST3H2BB, HSF4, IF144L, IF16, IGFBP3, KHDC1, KIF20A, LEF1, LOX, LY6E, MGAT4C, MMP3, MX1, NDNF, NDUFA4L2, NUSAP1, PDGFD, PHLDA1, PTX3, RGS18, SFRP4, TPBG and VCAN.

Example 13

H4 neuroglioma cells seeded in 96 well plates 5000 pr well were treated with 10 μM final concentration of compounds for 5 days in 200 μL full growth medium. Progranulin expression levels were evaluated in the media after dilution 1:8 by ELISA from Abcam (ab252364) according to manufactorer's protocol. Progranulins levels were normalized to PBS treated cells and values above >1 therefore indicates an upregulation of PGRN protein levels. Table 4 list the compounds tested, their sequences and their corresponding target site on the PGRN mRNA as well as the Progranulin protein expression levels.

Lengthy table referenced here

US20230287412A1-20230914-T00001

Please refer to the end of the specification for access instructions.

Lengthy table referenced here

US20230287412A1-20230914-T00002

Please refer to the end of the specification for access instructions.

LENGTHY TABLES

The patent application contains a lengthy table section. A copy of the table is available in electronic form from the USPTO web site (). An electronic copy of the table will also be available from the USPTO upon request and payment of the fee set forth in 37 CFR 1.19(b)(3).

Claims

1. An antisense oligonucleotide progranulin agonist, wherein the antisense oligonucleotide is 8-40 nucleotides in length and comprises a contiguous nucleotide sequence of 8-40 nucleotides in length which are complementary to a human progranulin precursor-mRNA (pre-mRNA) or mature mRNA transcript
2. The antisense oligonucleotide progranulin agonist of claim 1, wherein the human progranulin mature mRNA transcript is SEQ ID NO 1.
3. The antisense oligonucleotide progranulin agonist of claim 1, wherein the human progranulin precursor-mRNA (pre-mRNA) is SEQ ID NO 3949.
4. The antisense oligonucleotide progranulin agonist according to any one of claims 1-3, wherein the contiguous nucleotide sequence is of a length of at least 12 nucleotides in length.
5. The antisense oligonucleotide progranulin agonist according to claim 4, wherein the contiguous nucleotide sequence is 12-16 or 12-18 nucleotides in length.
6. The antisense oligonucleotide progranulin agonist according to claim 4, wherein the contiguous nucleotide sequence is 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40 nucleotides in length.
7. The antisense oligonucleotide progranulin agonist according to any one of claims 1-6, wherein the contiguous nucleotide sequence is the same length as the antisense oligonucleotide.
8. The antisense oligonucleotide progranulin agonist according to any one of claims 1-7, wherein the contiguous nucleotide sequence is fully complementary to the human progranulin precursor-mRNA (pre-mRNA) or mature mRNA transcript.
9. The antisense oligonucleotide progranulin agonist according to any one of claims 1-8, wherein the contiguous nucleotide sequence is complementary to a 5′UTR region of a human progranulin mature mRNA transcript.
10. The antisense oligonucleotide progranulin agonist according to claim 9, wherein the contiguous nucleotide sequence is complementary to SEQ ID NO 2, SEQ ID NO 689, SEQ ID NO 683, or a sequence selected from the group consisting of SEQ ID NO 343-586.
11. The antisense oligonucleotide progranulin agonist according to any one of claims 1-9, wherein the contiguous nucleotide sequence is complementary to nucleotides 38-246 of SEQ ID NO 1.
12. The antisense oligonucleotide progranulin agonist according to any one of claims 1-9, wherein the contiguous nucleotide sequence is fully complementary to SEQ ID NO 2, or SEQ ID NO 689.
13. The antisense oligonucleotide progranulin agonist according to any one of claims 1-9, wherein the contiguous nucleotide sequence is fully complementary to a sequence selected from the group consisting of SEQ ID NO 568, SEQ ID NO 571, SEQ ID NO 575, SEQ ID NO 576, SEQ ID NO 577, SEQ ID NO 578, SEQ ID NO 584 & SEQ ID NO 586.
14. The antisense oligonucleotide progranulin agonist according to any one of claims 1-13, wherein the contiguous nucleotide sequence is a sequence selected from the group consisting of SEQ ID NO 3-342, or at least 8 or at least 10 contiguous nucleotides thereof.
15. The antisense oligonucleotide progranulin agonist according to any one of claims 1-14, wherein the contiguous nucleotide sequence is selected from SEQ ID NO 105, SEQ ID NO 106, SEQ ID NO 110, SEQ ID NO 113, SEQ ID NO 114, SEQ ID NO 231 and SEQ ID NO 241 or at least 8 or at least 10 contiguous nucleotides thereof.
16. The antisense oligonucleotide progranulin agonist according to any one of claims 1-8, wherein contiguous nucleotide sequence is complementary to a 3′UTR region of a human progranulin mature mRNA transcript.
17. The antisense oligonucleotide progranulin agonist according to claim 16, wherein the contiguous nucleotide sequence is complementary to SEQ ID NO 684, SEQ ID NO 685, SEQ ID NO 686, SEQ ID NO 687, SEQ ID NO 688, or a sequence selected from the group consisting of SEQ ID NO 587-682.
18. The antisense oligonucleotide progranulin agonist according to claim 16, wherein the contiguous nucleotide sequence is complementary to nucleotides 2039-2346 of SEQ ID NO 1.
19. The antisense oligonucleotide progranulin agonist according to any one of claims 16-18 wherein the contiguous nucleotide sequence is fully complementary to a sequence selected from the group consisting of SEQ ID NO 684, SEQ ID NO 685, SEQ ID NO 686, SEQ ID NO 687, and SEQ ID NO 688.
20. The antisense oligonucleotide progranulin agonist according to any one of claims 16-19 wherein the contiguous nucleotide sequence is fully complementary to a sequence selected from the group consisting of SEQ ID NO 607, SEQ ID NO 608, SEQ ID NO 609, SEQ ID NO 610, SEQ ID NO 611, SEQ ID NO 612, SEQ ID NO 619, SEQ ID NO 620, SEQ ID NO 633, SEQ ID NO 640, SEQ ID NO 641, SEQ ID NO 645, SEQ ID NO 651, and SEQ ID NO 652.
21. The antisense oligonucleotide progranulin agonist according to any one of claims 16-20, wherein the contiguous nucleotide sequence is selected from SEQ ID NO 267, SEQ ID NO 268, SEQ ID NO 269, SEQ ID NO 270, SEQ ID NO 271, SEQ ID NO 272, SEQ ID NO 279, SEQ ID NO 280, SEQ ID NO 293, SEQ ID NO 300, SEQ ID NO 301, SEQ ID NO 305, SEQ ID NO 311, and SEQ ID NO 312, or at least 8 or at least 10 contiguous nucleotides thereof.
22. The antisense oligonucleotide progranulin agonist according to any one of claims 1-8, wherein the contiguous nucleotide sequence is complementary to a sequence selected from the group consisting of SEQ ID NO 2040-3386.
23. The antisense oligonucleotide progranulin agonist according to claim 22, wherein the contiguous nucleotide sequence is complementary to a sequence selected from the group consisting of SEQ ID 2321, SEQ ID 2322, SEQ ID 2324, SEQ ID 2328, SEQ ID 2329, SEQ ID 2331, SEQ ID 2334, SEQ ID 2335, SEQ ID 2336, SEQ ID 2337, SEQ ID 2338, SEQ ID 2339, SEQ ID 2340, SEQ ID 2341, SEQ ID 2342, SEQ ID 2345, SEQ ID 2346, SEQ ID 2347, SEQ ID 2348, SEQ ID 2349, SEQ ID 2350, SEQ ID 2351, SEQ ID 2352, SEQ ID 2353, SEQ ID 2354, SEQ ID 2355, SEQ ID 2356, SEQ ID 2357, SEQ ID 2358, SEQ ID 2359, SEQ ID 2360, SEQ ID 2361, SEQ ID 2362, SEQ ID 2364, SEQ ID 2365, SEQ ID 2366, SEQ ID 2367, SEQ ID 2368, SEQ ID 2369, SEQ ID 2370, SEQ ID 2371, SEQ ID 2372, SEQ ID 2373, SEQ ID 2374, SEQ ID 2375, SEQ ID 2376, SEQ ID 2377, SEQ ID 2378, SEQ ID 2379, SEQ ID 2380, SEQ ID 2381, SEQ ID 2384, SEQ ID 2386, SEQ ID 2387, SEQ ID 2388, SEQ ID 2389, SEQ ID 2390, SEQ ID 2392, SEQ ID 2393, SEQ ID 2394, SEQ ID 2395, SEQ ID 2396, SEQ ID 2397, SEQ ID 2398, SEQ ID 2399, SEQ ID 2400, SEQ ID 2401, SEQ ID 2403, SEQ ID 2404, SEQ ID 2405, SEQ ID 2406, SEQ ID 2407, SEQ ID 2408, SEQ ID 2410, SEQ ID 2411, SEQ ID 2413, SEQ ID 2414, SEQ ID 2415, SEQ ID 2416, SEQ ID 2418, SEQ ID 2419, SEQ ID 2421, SEQ ID 2424, SEQ ID 2425, SEQ ID 2426, SEQ ID 2427, SEQ ID 2428, SEQ ID 2429, SEQ ID 2430, SEQ ID 2431, SEQ ID 2432, SEQ ID 2433, SEQ ID 2434, SEQ ID 2435, SEQ ID 2436, SEQ ID 2437, SEQ ID 2438, SEQ ID 2439, SEQ ID 2440, SEQ ID 2441, SEQ ID 2442, SEQ ID 2443, SEQ ID 2444, SEQ ID 2445, SEQ ID 2446, SEQ ID 2447, SEQ ID 2448, SEQ ID 2449, SEQ ID 2450, SEQ ID 2451, SEQ ID 2452, SEQ ID 2453, SEQ ID 2454, SEQ ID 2455, SEQ ID 2456, SEQ ID 2457, SEQ ID 2458, SEQ ID 2459, SEQ ID 2460, SEQ ID 2461, SEQ ID 2462, SEQ ID 2463, SEQ ID 2464, SEQ ID 2465, SEQ ID 2466, SEQ ID 2467, SEQ ID 2468, SEQ ID 2469, SEQ ID 2470, SEQ ID 2471, SEQ ID 2472, SEQ ID 2473, SEQ ID 2474, SEQ ID 2475, SEQ ID 2476, SEQ ID 2477, SEQ ID 2478, SEQ ID 2479, SEQ ID 2481, SEQ ID 2482, SEQ ID 2483, SEQ ID 2484, SEQ ID 2485, SEQ ID 2487, SEQ ID 2489, SEQ ID 2490, SEQ ID 2491, SEQ ID 2492, SEQ ID 2493, SEQ ID 2494, SEQ ID 2495, SEQ ID 2496, SEQ ID 2497, SEQ ID 2498, SEQ ID 2499, SEQ ID 2501, SEQ ID 2502, SEQ ID 2503, SEQ ID 2504, SEQ ID 2505, SEQ ID 2506, SEQ ID 2507, SEQ ID 2508, SEQ ID 2509, SEQ ID 2510, SEQ ID 2511, SEQ ID 2512, SEQ ID 2513, SEQ ID 2514, SEQ ID 2515, SEQ ID 2516, SEQ ID 2518, SEQ ID 2519, SEQ ID 2520, SEQ ID 2521, SEQ ID 2522, SEQ ID 2523, SEQ ID 2524, SEQ ID 2525, SEQ ID 2526, SEQ ID 2527, SEQ ID 2528, SEQ ID 2531, SEQ ID 2533, SEQ ID 2534, SEQ ID 2535, SEQ ID 2536, SEQ ID 2537, SEQ ID 2538, SEQ ID 2540, SEQ ID 2541, SEQ ID 2542, SEQ ID 2544, SEQ ID 2546, SEQ ID 2547, SEQ ID 2549, SEQ ID 2550, SEQ ID 2551, SEQ ID 2553, SEQ ID 2554, SEQ ID 2555, SEQ ID 2556, SEQ ID 2557, SEQ ID 2560, SEQ ID 2561, SEQ ID 2562, SEQ ID 2563, SEQ ID 2565, SEQ ID 2566, SEQ ID 2567, SEQ ID 2572, SEQ ID 2573, SEQ ID 2574, SEQ ID 2575, SEQ ID 2576, SEQ ID 2577, SEQ ID 2578, SEQ ID 2579, SEQ ID 2580, SEQ ID 2581, SEQ ID 2582, SEQ ID 2583, SEQ ID 2584, SEQ ID 2585, SEQ ID 2586, SEQ ID 2588, SEQ ID 2589, SEQ ID 2590, SEQ ID 2591, SEQ ID 2592, SEQ ID 2593, SEQ ID 2594, SEQ ID 2595, SEQ ID 2596, SEQ ID 2597, SEQ ID 2598, SEQ ID 2599, SEQ ID 2601, SEQ ID 2602, SEQ ID 2603, SEQ ID 2604, SEQ ID 2606, SEQ ID 2610, SEQ ID 2613, SEQ ID 2614, SEQ ID 2615, SEQ ID 2619, SEQ ID 2622, SEQ ID 2623, SEQ ID 2624, SEQ ID 2625, SEQ ID 2626, SEQ ID 2627, SEQ ID 2628, SEQ ID 2629, SEQ ID 2630, SEQ ID 2631, SEQ ID 2632, SEQ ID 2633, SEQ ID 2634, SEQ ID 2635, SEQ ID 2636, SEQ ID 2637, SEQ ID 2638, SEQ ID 2639, SEQ ID 2640, SEQ ID 2641, SEQ ID 2642, SEQ ID 2643, SEQ ID 2644, SEQ ID 2645, SEQ ID 2646, SEQ ID 2647, SEQ ID 2648, SEQ ID 2649, SEQ ID 2650, SEQ ID 2651, SEQ ID 2652, SEQ ID 2653, SEQ ID 2654, SEQ ID 2655, SEQ ID 2656, SEQ ID 2658, SEQ ID 2659, SEQ ID 2660, SEQ ID 2661, SEQ ID 2662, SEQ ID 2663, SEQ ID 2664, SEQ ID 2665, SEQ ID 2666, SEQ ID 2667, SEQ ID 2668, SEQ ID 2669, SEQ ID 2670, SEQ ID 2671, SEQ ID 2672, SEQ ID 2673, SEQ ID 2674, SEQ ID 2675, SEQ ID 2676, SEQ ID 2677, SEQ ID 2678, SEQ ID 2679, SEQ ID 2680, SEQ ID 2681, SEQ ID 2682, SEQ ID 2683, SEQ ID 2684, SEQ ID 2685, SEQ ID 2686, SEQ ID 2687, SEQ ID 2688, SEQ ID 2689, SEQ ID 2690, SEQ ID 2691, SEQ ID 2693, SEQ ID 2694, SEQ ID 2695, SEQ ID 2696, SEQ ID 2697, SEQ ID 2698, SEQ ID 2699, SEQ ID 2700, SEQ ID 2701, SEQ ID 2702, SEQ ID 2703, SEQ ID 2704, SEQ ID 2705, SEQ ID 2706, SEQ ID 2707, SEQ ID 2708, SEQ ID 2709, SEQ ID 2710, SEQ ID 2711, SEQ ID 2712, SEQ ID 2713, SEQ ID 2714, SEQ ID 2715, SEQ ID 2716, SEQ ID 2717, SEQ ID 2718, SEQ ID 2719, SEQ ID 2720, SEQ ID 2721, SEQ ID 2722, SEQ ID 2723, SEQ ID 2726, SEQ ID 2727, SEQ ID 2728, SEQ ID 2729, SEQ ID 2730, SEQ ID 2733, SEQ ID 2734, SEQ ID 2735, SEQ ID 2736, SEQ ID 2737, SEQ ID 2738, SEQ ID 2739, SEQ ID 2740, SEQ ID 2741, SEQ ID 2742, SEQ ID 2743, SEQ ID 2744, SEQ ID 2745, SEQ ID 2746, SEQ ID 2747, SEQ ID 2748, SEQ ID 2749, SEQ ID 2750, SEQ ID 2751, SEQ ID 2752, SEQ ID 2753, SEQ ID 2754, SEQ ID 2755, SEQ ID 2756, SEQ ID 2757, SEQ ID 2758, SEQ ID 2759, SEQ ID 2760, SEQ ID 2761, SEQ ID 2762, SEQ ID 2763, SEQ ID 2764, SEQ ID 2765, SEQ ID 2766, SEQ ID 2767, SEQ ID 2768, SEQ ID 2769, SEQ ID 2770, SEQ ID 2771, SEQ ID 2772, SEQ ID 2773, SEQ ID 2774, SEQ ID 2775, SEQ ID 2815, SEQ ID 2816, SEQ ID 2817, SEQ ID 2818, SEQ ID 2819, SEQ ID 2820, SEQ ID 2821, SEQ ID 2822, SEQ ID 2823, SEQ ID 2824, SEQ ID 2825, SEQ ID 2826, SEQ ID 2827, SEQ ID 2828, SEQ ID 2829, SEQ ID 2830, SEQ ID 2831, SEQ ID 2832, SEQ ID 2833, SEQ ID 2834, SEQ ID 2835, SEQ ID 2836, SEQ ID 2837, SEQ ID 2838, SEQ ID 2839, SEQ ID 2840, SEQ ID 2841, SEQ ID 2842, SEQ ID 2843, SEQ ID 2844, SEQ ID 2845, SEQ ID 2847, SEQ ID 2848, SEQ ID 2849, SEQ ID 2850, SEQ ID 2851, SEQ ID 2852, SEQ ID 2853, SEQ ID 2854, SEQ ID 2855, SEQ ID 2858, SEQ ID 2859, SEQ ID 2860, SEQ ID 2861, SEQ ID 2862, SEQ ID 2863, SEQ ID 2864, SEQ ID 2865, SEQ ID 2866, SEQ ID 2867, SEQ ID 2868, SEQ ID 2869, SEQ ID 2870, SEQ ID 2871, SEQ ID 2872, SEQ ID 2873, SEQ ID 2874, SEQ ID 2875, SEQ ID 2876, SEQ ID 2878, SEQ ID 2879, SEQ ID 2880, SEQ ID 2881, SEQ ID 2882, SEQ ID 2883, SEQ ID 2884, SEQ ID 2885, SEQ ID 2886, SEQ ID 2887, SEQ ID 2888, SEQ ID 2889, SEQ ID 2890, SEQ ID 2891, SEQ ID 2892, SEQ ID 2893, SEQ ID 2894, SEQ ID 2895, SEQ ID 2896, SEQ ID 2897, SEQ ID 2898, SEQ ID 2899, SEQ ID 2900, SEQ ID 2901, SEQ ID 2902, SEQ ID 2903, SEQ ID 2904, SEQ ID 2905, SEQ ID 2906, SEQ ID 2907, SEQ ID 2908, SEQ ID 2909, SEQ ID 2910, SEQ ID 2911, SEQ ID 2912, SEQ ID 2913, SEQ ID 2914, SEQ ID 2915, SEQ ID 2916, SEQ ID 2917, SEQ ID 2918, SEQ ID 2919, SEQ ID 2920, SEQ ID 2921, SEQ ID 2922, SEQ ID 2923, SEQ ID 2924, SEQ ID 2925, SEQ ID 2926, SEQ ID 2927, SEQ ID 2928, SEQ ID 2929, SEQ ID 2930, SEQ ID 2931, SEQ ID 2932, SEQ ID 2934, SEQ ID 2935, SEQ ID 2936, SEQ ID 2937, SEQ ID 2938, SEQ ID 2939, SEQ ID 2940, SEQ ID 2941, SEQ ID 2942, SEQ ID 2943, SEQ ID 2944, SEQ ID 2945, SEQ ID 2946, SEQ ID 2947, SEQ ID 2948, SEQ ID 2949, SEQ ID 2950, SEQ ID 2951, SEQ ID 2953, SEQ ID 2954, SEQ ID 2955, SEQ ID 2956, SEQ ID 2957, SEQ ID 2958, SEQ ID 2960, SEQ ID 2961, SEQ ID 2963, SEQ ID 2964, SEQ ID 2965, SEQ ID 2966, SEQ ID 2967, SEQ ID 2969, SEQ ID 2970, SEQ ID 2971, SEQ ID 2972, SEQ ID 2973, SEQ ID 2974, SEQ ID 2975, SEQ ID 2976, SEQ ID 2977, SEQ ID 2978, SEQ ID 2979, SEQ ID 2980, SEQ ID 2981, SEQ ID 2982, SEQ ID 2983, SEQ ID 2984, SEQ ID 2985, SEQ ID 3053, SEQ ID 3054, SEQ ID 3055, SEQ ID 3056, SEQ ID 3057, SEQ ID 3058, SEQ ID 3059, SEQ ID 3060, SEQ ID 3061, SEQ ID 3062, SEQ ID 3063, SEQ ID 3064, SEQ ID 3065, SEQ ID 3066, SEQ ID 3068, SEQ ID 3069, SEQ ID 3070, SEQ ID 3071, SEQ ID 3072, SEQ ID 3073, SEQ ID 3074, SEQ ID 3075, SEQ ID 3076, SEQ ID 3077, SEQ ID 3078, SEQ ID 3079, SEQ ID 3080, SEQ ID 3081, SEQ ID 3082, SEQ ID 3083, SEQ ID 3084, SEQ ID 3085, SEQ ID 3086, SEQ ID 3087, SEQ ID 3088, SEQ ID 3089, SEQ ID 3090, SEQ ID 3091, SEQ ID 3092, SEQ ID 3093, SEQ ID 3094, SEQ ID 3095, SEQ ID 3097, SEQ ID 3098, SEQ ID 3099, SEQ ID 3100, SEQ ID 3102, SEQ ID 3103, SEQ ID 3104, SEQ ID 3105, SEQ ID 3106, SEQ ID 3107, SEQ ID 3108, SEQ ID 3109, SEQ ID 3110, SEQ ID 3112, SEQ ID 3113, SEQ ID 3115, SEQ ID 3116, SEQ ID 3117, SEQ ID 3119, SEQ ID 3120, SEQ ID 3121, SEQ ID 3122, SEQ ID 3123, SEQ ID 3124, SEQ ID 3125, SEQ ID 3126, SEQ ID 3127, SEQ ID 3128, SEQ ID 3129, SEQ ID 3130, SEQ ID 3131, SEQ ID 3132, SEQ ID 3133, SEQ ID 3134, SEQ ID 3135, SEQ ID 3136, SEQ ID 3137, SEQ ID 3138, SEQ ID 3139, SEQ ID 3140, SEQ ID 3141, SEQ ID 3142, SEQ ID 3143, SEQ ID 3144, SEQ ID 3145, SEQ ID 3146, SEQ ID 3147, SEQ ID 3148, SEQ ID 3149, SEQ ID 3150, SEQ ID 3151, SEQ ID 3152, SEQ ID 3153, SEQ ID 3154, SEQ ID 3155, SEQ ID 3156, SEQ ID 3157, SEQ ID 3158, SEQ ID 3159, SEQ ID 3160, SEQ ID 3161, SEQ ID 3162, SEQ ID 3163, SEQ ID 3164, SEQ ID 3165, SEQ ID 3166, SEQ ID 3167, SEQ ID 3168, SEQ ID 3169, SEQ ID 3170, SEQ ID 3171, SEQ ID 3172, SEQ ID 3173, SEQ ID 3174, SEQ ID 3175, SEQ ID 3176, SEQ ID 3177, SEQ ID 3178, SEQ ID 3179, SEQ ID 3180, SEQ ID 3181, SEQ ID 3182, SEQ ID 3183, SEQ ID 3184, SEQ ID 3185, SEQ ID 3186, SEQ ID 3187, SEQ ID 3188, SEQ ID 3189, SEQ ID 3190, SEQ ID 3191, SEQ ID 3192, SEQ ID 3193, SEQ ID 3194, SEQ ID 3195, SEQ ID 3196, SEQ ID 3197, SEQ ID 3198, SEQ ID 3199, SEQ ID 3200, SEQ ID 3201, SEQ ID 3202, SEQ ID 3203, SEQ ID 3204, SEQ ID 3205, SEQ ID 3206, SEQ ID 3207, SEQ ID 3208, SEQ ID 3209, SEQ ID 3210, SEQ ID 3211, SEQ ID 3212, SEQ ID 3213, SEQ ID 3214, SEQ ID 3215, SEQ ID 3216, SEQ ID 3217, SEQ ID 3218, SEQ ID 3219, SEQ ID 3220, SEQ ID 3221, SEQ ID 3222, SEQ ID 3223, SEQ ID 3224, SEQ ID 3225, SEQ ID 3226, SEQ ID 3227, SEQ ID 3228, SEQ ID 3229, SEQ ID 3230, SEQ ID 3231, SEQ ID 3232, SEQ ID 3233, SEQ ID 3234, SEQ ID 3235, SEQ ID 3236, SEQ ID 3237, SEQ ID 3238, SEQ ID 3239, SEQ ID 3240, SEQ ID 3241, SEQ ID 3242, SEQ ID 3243, SEQ ID 3244, SEQ ID 3245, SEQ ID 3246, SEQ ID 3248, SEQ ID 3249, SEQ ID 3250, SEQ ID 3251, SEQ ID 3252, SEQ ID 3253, SEQ ID 3254, SEQ ID 3255, SEQ ID 3256, SEQ ID 3257, SEQ ID 3258, SEQ ID 3259, SEQ ID 3260, SEQ ID 3261, SEQ ID 3262, SEQ ID 3263, SEQ ID 3264, SEQ ID 3265, SEQ ID 3266, SEQ ID 3267, SEQ ID 3268, SEQ ID 3269, SEQ ID 3270, SEQ ID 3271, SEQ ID 3272, SEQ ID 3273, SEQ ID 3275, SEQ ID 3276, SEQ ID 3277, SEQ ID 3278, SEQ ID 3279, SEQ ID 3280, SEQ ID 3282, SEQ ID 3284, SEQ ID 3285, SEQ ID 3286, SEQ ID 3287, SEQ ID 3288, SEQ ID 3289, SEQ ID 3291, SEQ ID 3292, SEQ ID 3293, SEQ ID 3294, SEQ ID 3295, SEQ ID 3296, SEQ ID 3297, SEQ ID 3298, SEQ ID 3299, SEQ ID 3300, SEQ ID 3301, SEQ ID 3302, SEQ ID 3303, SEQ ID 3304, SEQ ID 3305, SEQ ID 3306, SEQ ID 3307, SEQ ID 3308, SEQ ID 3309, SEQ ID 3310, SEQ ID 3311, SEQ ID 3312, SEQ ID 3313, SEQ ID 3314, SEQ ID 3315, SEQ ID 3316, SEQ ID 3317, SEQ ID 3318, SEQ ID 3320, SEQ ID 3321, SEQ ID 3322, SEQ ID 3323, SEQ ID 3324, SEQ ID 3325, SEQ ID 3326, SEQ ID 3327, SEQ ID 3329, SEQ ID 3331, SEQ ID 3332, SEQ ID 3333, SEQ ID 3334, SEQ ID 3335, SEQ ID 3336, SEQ ID 3337, SEQ ID 3338, SEQ ID 3339, SEQ ID 3340, SEQ ID 3342, SEQ ID 3343, SEQ ID 3344, SEQ ID 3345, SEQ ID 3346, SEQ ID 3347, SEQ ID 3348, SEQ ID 3349, SEQ ID 3350, SEQ ID 3351, SEQ ID 3352, SEQ ID 3353, SEQ ID 3354, SEQ ID 3355, SEQ ID 3356, SEQ ID 3357, SEQ ID 3358, SEQ ID 3359, SEQ ID 3360, SEQ ID 3361, SEQ ID 3362, SEQ ID 3363, SEQ ID 3364, SEQ ID 3365, SEQ ID 3366, SEQ ID 3367, SEQ ID 3368, SEQ ID 3369, SEQ ID 3370, SEQ ID 3371, SEQ ID 3390, SEQ ID 3391, SEQ ID 3392, SEQ ID 3393, SEQ ID 3394, SEQ ID 3395, SEQ ID 3396, SEQ ID 3397, SEQ ID 3398, SEQ ID 3399, SEQ ID 3400, SEQ ID 3401, SEQ ID 3402, SEQ ID 3403, SEQ ID 3404, SEQ ID 3405, SEQ ID 3406, SEQ ID 3407, SEQ ID 3408, SEQ ID 3409, SEQ ID 3410, SEQ ID 3411, SEQ ID 3412, SEQ ID 3413, SEQ ID 3414, SEQ ID 3415, SEQ ID 3416, SEQ ID 3417, SEQ ID 3418, SEQ ID 3419, SEQ ID 3420, SEQ ID 3421, SEQ ID 3422, SEQ ID 3423, SEQ ID 3424, SEQ ID 3425, SEQ ID 3426, SEQ ID 3427, SEQ ID 3428, SEQ ID 3429, SEQ ID 3430, SEQ ID 3431, SEQ ID 3432, SEQ ID 3433, SEQ ID 3434, SEQ ID 3435, SEQ ID 3436, SEQ ID 3437, SEQ ID 3438, SEQ ID 3439, SEQ ID 3440, SEQ ID 3441, SEQ ID 3442, SEQ ID 3443, SEQ ID 3444, SEQ ID 3445, SEQ ID 3446, SEQ ID 3447, SEQ ID 3448, SEQ ID 3449, SEQ ID 3450, SEQ ID 3451, SEQ ID 3452, SEQ ID 3453, SEQ ID 3454, SEQ ID 3460, SEQ ID 3461, SEQ ID 3464, SEQ ID 3465, SEQ ID 3466, SEQ ID 3467, SEQ ID 3468, SEQ ID 3486, SEQ ID 3487, SEQ ID 3488, SEQ ID 3489, SEQ ID 3490, SEQ ID 3491, SEQ ID 3493, SEQ ID 3494, SEQ ID 3496, SEQ ID 3497, SEQ ID 3501, SEQ ID 3505, SEQ ID 3508, SEQ ID 3511, SEQ ID 3512, SEQ ID 3516, SEQ ID 3517, SEQ ID 3518, SEQ ID 3521, SEQ ID 3522, SEQ ID 3523, SEQ ID 3524, SEQ ID 3525, SEQ ID 3526, SEQ ID 3527, SEQ ID 3528, SEQ ID 3530, SEQ ID 3531, SEQ ID 3532, SEQ ID 3534, SEQ ID 3535, SEQ ID 3536, SEQ ID 3538, SEQ ID 3539, SEQ ID 3541, SEQ ID 3542, SEQ ID 3543, SEQ ID 3544, SEQ ID 3546, SEQ ID 3548, SEQ ID 3549, SEQ ID 3550, SEQ ID 3552, SEQ ID 3556, SEQ ID 3557, SEQ ID 3558, SEQ ID 3560, SEQ ID 3561, SEQ ID 3566, SEQ ID 3567, SEQ ID 3568, SEQ ID 3569, SEQ ID 3571, SEQ ID 3572, SEQ ID 3573, SEQ ID 3574, SEQ ID 3576, SEQ ID 3577, SEQ ID 3578, SEQ ID 3580, SEQ ID 3581, SEQ ID 3584, SEQ ID 3585, SEQ ID 3586, SEQ ID 3588, SEQ ID 3590, SEQ ID 3592, SEQ ID 3594, SEQ ID 3595, SEQ ID 3598, SEQ ID 3599, SEQ ID 3600, SEQ ID 3601, SEQ ID 3602, SEQ ID 3603, SEQ ID 3605, SEQ ID 3607, SEQ ID 3609, SEQ ID 3610, SEQ ID 3613, SEQ ID 3614, SEQ ID 3615, SEQ ID 3616, SEQ ID 3617, SEQ ID 3621, SEQ ID 3623, SEQ ID 3624, SEQ ID 3625, SEQ ID 3626, SEQ ID 3627, SEQ ID 3628, SEQ ID 3629, SEQ ID 3630, SEQ ID 3631, SEQ ID 3632, SEQ ID 3633, SEQ ID 3636, SEQ ID 3637, SEQ ID 3638, SEQ ID 3639, SEQ ID 3641, SEQ ID 3642, SEQ ID 3643, SEQ ID 3645, SEQ ID 3647, SEQ ID 3648, SEQ ID 3649, SEQ ID 3651, SEQ ID 3654, SEQ ID 3656, SEQ ID 3659, SEQ ID 3660, SEQ ID 3661, SEQ ID 3663, SEQ ID 3664, SEQ ID 3665, SEQ ID 3666, SEQ ID 3670, SEQ ID 3672, SEQ ID 3676, SEQ ID 3678, SEQ ID 3679, SEQ ID 3680, SEQ ID 3681, SEQ ID 3682, SEQ ID 3683, SEQ ID 3684, SEQ ID 3685, SEQ ID 3686, SEQ ID 3687, SEQ ID 3688, SEQ ID 3689, SEQ ID 3690, SEQ ID 3691, SEQ ID 3692, SEQ ID 3693, SEQ ID 3694, SEQ ID 3695, SEQ ID 3696, SEQ ID 3697, SEQ ID 3698, SEQ ID 3699, SEQ ID 3700, SEQ ID 3701, SEQ ID 3702, SEQ ID 3703, SEQ ID 3704, SEQ ID 3705, SEQ ID 3706, SEQ ID 3707, SEQ ID 3708, SEQ ID 3709, SEQ ID 3710, SEQ ID 3711, SEQ ID 3712, SEQ ID 3713, SEQ ID 3714, SEQ ID 3715, SEQ ID 3716, SEQ ID 3717, SEQ ID 3718, SEQ ID 3719, SEQ ID 3720, SEQ ID 3721, SEQ ID 3722, SEQ ID 3723, SEQ ID 3724, SEQ ID 3725, SEQ ID 3726, SEQ ID 3727, SEQ ID 3729, SEQ ID 3730, SEQ ID 3731, SEQ ID 3732, SEQ ID 3733, SEQ ID 3734, SEQ ID 3735, SEQ ID 3736, SEQ ID 3737, SEQ ID 3738, SEQ ID 3739, SEQ ID 3740, SEQ ID 3741, SEQ ID 3742, SEQ ID 3743, SEQ ID 3744, SEQ ID 3745, SEQ ID 3746, SEQ ID 3747, SEQ ID 3748, SEQ ID 3749, SEQ ID 3750, SEQ ID 3751, SEQ ID 3752, SEQ ID 3753, SEQ ID 3754, SEQ ID 3755, SEQ ID 3774, SEQ ID 3775, SEQ ID 3776, SEQ ID 3777, SEQ ID 3778, SEQ ID 3779, SEQ ID 3780, SEQ ID 3781, SEQ ID 3782, SEQ ID 3783, SEQ ID 3784, SEQ ID 3785, SEQ ID 3786, SEQ ID 3787, SEQ ID 3788, SEQ ID 3789, SEQ ID 3790, SEQ ID 3791, SEQ ID 3792, SEQ ID 3793, SEQ ID 3794, SEQ ID 3795, SEQ ID 3796, SEQ ID 3797, SEQ ID 3798, SEQ ID 3799, SEQ ID 3800, SEQ ID 3801, SEQ ID 3802, SEQ ID 3803, SEQ ID 3804, SEQ ID 3805, SEQ ID 3806, SEQ ID 3807, SEQ ID 3808, SEQ ID 3809, SEQ ID 3810, SEQ ID 3811, SEQ ID 3812, SEQ ID 3813, SEQ ID 3814, SEQ ID 3815, SEQ ID 3816, SEQ ID 3817, SEQ ID 3818, SEQ ID 3819, SEQ ID 3820, SEQ ID 3821, SEQ ID 3822, SEQ ID 3823, SEQ ID 3824, SEQ ID 3825, SEQ ID 3826, SEQ ID 3827, SEQ ID 3828, SEQ ID 3829, SEQ ID 3830, SEQ ID 3831, SEQ ID 3832, SEQ ID 3833, SEQ ID 3834, SEQ ID 3835, SEQ ID 3836, SEQ ID 3837, SEQ ID 3838, SEQ ID 3839, SEQ ID 3840, SEQ ID 3841, SEQ ID 3842, SEQ ID 3844, SEQ ID 3848, SEQ ID 3850, SEQ ID 3851, SEQ ID 3852, SEQ ID 3853, SEQ ID 3867, SEQ ID 3868, SEQ ID 3869, SEQ ID 3870, SEQ ID 3871, SEQ ID 3872, SEQ ID 3873, SEQ ID 3874, SEQ ID 3875, SEQ ID 3876, SEQ ID 3877, SEQ ID 3878, SEQ ID 3879, SEQ ID 3880, SEQ ID 3881, SEQ ID 3882, SEQ ID 3883, SEQ ID 3884, SEQ ID 3885, SEQ ID 3886, SEQ ID 3887, SEQ ID 3888, SEQ ID 3889, SEQ ID 3890, SEQ ID 3891, SEQ ID 3892, SEQ ID 3893, SEQ ID 3894, SEQ ID 3895, SEQ ID 3896, SEQ ID 3897, SEQ ID 3898, SEQ ID 3899, SEQ ID 3900, SEQ ID 3901, SEQ ID 3902, SEQ ID 3903, SEQ ID 3904, SEQ ID 3905, SEQ ID 3906, SEQ ID 3907, SEQ ID 3908, SEQ ID 3909, SEQ ID 3910, SEQ ID 3911, SEQ ID 3912, SEQ ID 3913, SEQ ID 3914, SEQ ID 3915, SEQ ID 3916, SEQ ID 3917, SEQ ID 3918, SEQ ID 3919, SEQ ID 3920, SEQ ID 3921, SEQ ID 3922, SEQ ID 3923, SEQ ID 3924, SEQ ID 3925, SEQ ID 3926, SEQ ID 3927, SEQ ID 3928, SEQ ID 3929, SEQ ID 3930, SEQ ID 3931, SEQ ID 3932, SEQ ID 3933, SEQ ID 3934, SEQ ID 3935, SEQ ID 3936, SEQ ID 3937, SEQ ID 3938, SEQ ID 3939, SEQ ID 3940, SEQ ID 3941, SEQ ID 3942, SEQ ID 3943, SEQ ID 3944, SEQ ID 3945, SEQ ID 3946, SEQ ID 3947, and SEQ ID 3948.
24. The antisense oligonucleotide progranulin agonist according to claim 22, wherein the contiguous nucleotide sequence is complementary to a sequence selected from the group consisting of SEQ ID 2321, SEQ ID 2335, SEQ ID 2336, SEQ ID 2337, SEQ ID 2338, SEQ ID 2339, SEQ ID 2348, SEQ ID 2349, SEQ ID 2351, SEQ ID 2352, SEQ ID 2353, SEQ ID 2354, SEQ ID 2355, SEQ ID 2358, SEQ ID 2360, SEQ ID 2364, SEQ ID 2365, SEQ ID 2366, SEQ ID 2367, SEQ ID 2369, SEQ ID 2371, SEQ ID 2373, SEQ ID 2375, SEQ ID 2386, SEQ ID 2387, SEQ ID 2388, SEQ ID 2389, SEQ ID 2394, SEQ ID 2403, SEQ ID 2426, SEQ ID 2428, SEQ ID 2429, SEQ ID 2430, SEQ ID 2431, SEQ ID 2432, SEQ ID 2435, SEQ ID 2440, SEQ ID 2441, SEQ ID 2442, SEQ ID 2444, SEQ ID 2446, SEQ ID 2447, SEQ ID 2450, SEQ ID 2451, SEQ ID 2452, SEQ ID 2453, SEQ ID 2454, SEQ ID 2455, SEQ ID 2456, SEQ ID 2458, SEQ ID 2459, SEQ ID 2461, SEQ ID 2463, SEQ ID 2464, SEQ ID 2465, SEQ ID 2466, SEQ ID 2467, SEQ ID 2468, SEQ ID 2469, SEQ ID 2470, SEQ ID 2471, SEQ ID 2472, SEQ ID 2473, SEQ ID 2474, SEQ ID 2475, SEQ ID 2476, SEQ ID 2477, SEQ ID 2478, SEQ ID 2482, SEQ ID 2483, SEQ ID 2484, SEQ ID 2485, SEQ ID 2487, SEQ ID 2489, SEQ ID 2494, SEQ ID 2495, SEQ ID 2496, SEQ ID 2497, SEQ ID 2499, SEQ ID 2501, SEQ ID 2502, SEQ ID 2504, SEQ ID 2506, SEQ ID 2507, SEQ ID 2508, SEQ ID 2509, SEQ ID 2511, SEQ ID 2513, SEQ ID 2515, SEQ ID 2516, SEQ ID 2518, SEQ ID 2519, SEQ ID 2520, SEQ ID 2521, SEQ ID 2523, SEQ ID 2525, SEQ ID 2534, SEQ ID 2537, SEQ ID 2544, SEQ ID 2546, SEQ ID 2554, SEQ ID 2555, SEQ ID 2556, SEQ ID 2560, SEQ ID 2561, SEQ ID 2562, SEQ ID 2595, SEQ ID 2626, SEQ ID 2628, SEQ ID 2629, SEQ ID 2630, SEQ ID 2631, SEQ ID 2633, SEQ ID 2638, SEQ ID 2639, SEQ ID 2640, SEQ ID 2649, SEQ ID 2651, SEQ ID 2652, SEQ ID 2655, SEQ ID 2658, SEQ ID 2665, SEQ ID 2666, SEQ ID 2667, SEQ ID 2669, SEQ ID 2670, SEQ ID 2676, SEQ ID 2677, SEQ ID 2678, SEQ ID 2679, SEQ ID 2682, SEQ ID 2686, SEQ ID 2688, SEQ ID 2689, SEQ ID 2691, SEQ ID 2694, SEQ ID 2698, SEQ ID 2699, SEQ ID 2700, SEQ ID 2701, SEQ ID 2703, SEQ ID 2706, SEQ ID 2709, SEQ ID 2711, SEQ ID 2712, SEQ ID 2713, SEQ ID 2714, SEQ ID 2719, SEQ ID 2720, SEQ ID 2721, SEQ ID 2737, SEQ ID 2739, SEQ ID 2740, SEQ ID 2741, SEQ ID 2742, SEQ ID 2743, SEQ ID 2744, SEQ ID 2745, SEQ ID 2746, SEQ ID 2747, SEQ ID 2748, SEQ ID 2749, SEQ ID 2750, SEQ ID 2751, SEQ ID 2752, SEQ ID 2753, SEQ ID 2754, SEQ ID 2755, SEQ ID 2756, SEQ ID 2757, SEQ ID 2758, SEQ ID 2760, SEQ ID 2763, SEQ ID 2764, SEQ ID 2765, SEQ ID 2766, SEQ ID 2767, SEQ ID 2768, SEQ ID 2769, SEQ ID 2770, SEQ ID 2771, SEQ ID 2772, SEQ ID 2774, SEQ ID 2816, SEQ ID 2817, SEQ ID 2818, SEQ ID 2819, SEQ ID 2820, SEQ ID 2824, SEQ ID 2828, SEQ ID 2829, SEQ ID 2830, SEQ ID 2831, SEQ ID 2832, SEQ ID 2833, SEQ ID 2834, SEQ ID 2835, SEQ ID 2836, SEQ ID 2837, SEQ ID 2851, SEQ ID 2852, SEQ ID 2866, SEQ ID 2871, SEQ ID 2872, SEQ ID 2886, SEQ ID 2887, SEQ ID 2890, SEQ ID 2891, SEQ ID 2892, SEQ ID 2895, SEQ ID 2896, SEQ ID 2899, SEQ ID 2904, SEQ ID 2910, SEQ ID 2911, SEQ ID 2912, SEQ ID 2913, SEQ ID 2914, SEQ ID 2916, SEQ ID 2918, SEQ ID 2919, SEQ ID 2920, SEQ ID 2922, SEQ ID 2925, SEQ ID 2926, SEQ ID 2932, SEQ ID 2939, SEQ ID 2941, SEQ ID 2942, SEQ ID 2943, SEQ ID 2972, SEQ ID 2973, SEQ ID 2974, SEQ ID 2975, SEQ ID 2976, SEQ ID 2977, SEQ ID 2980, SEQ ID 2983, SEQ ID 2985, SEQ ID 3053, SEQ ID 3054, SEQ ID 3055, SEQ ID 3056, SEQ ID 3058, SEQ ID 3059, SEQ ID 3060, SEQ ID 3061, SEQ ID 3062, SEQ ID 3063, SEQ ID 3064, SEQ ID 3065, SEQ ID 3066, SEQ ID 3068, SEQ ID 3069, SEQ ID 3070, SEQ ID 3071, SEQ ID 3072, SEQ ID 3073, SEQ ID 3074, SEQ ID 3075, SEQ ID 3076, SEQ ID 3077, SEQ ID 3078, SEQ ID 3079, SEQ ID 3082, SEQ ID 3083, SEQ ID 3084, SEQ ID 3085, SEQ ID 3088, SEQ ID 3089, SEQ ID 3090, SEQ ID 3091, SEQ ID 3092, SEQ ID 3095, SEQ ID 3097, SEQ ID 3102, SEQ ID 3106, SEQ ID 3108, SEQ ID 3110, SEQ ID 3116, SEQ ID 3120, SEQ ID 3121, SEQ ID 3125, SEQ ID 3126, SEQ ID 3133, SEQ ID 3134, SEQ ID 3135, SEQ ID 3137, SEQ ID 3138, SEQ ID 3140, SEQ ID 3141, SEQ ID 3142, SEQ ID 3143, SEQ ID 3145, SEQ ID 3148, SEQ ID 3152, SEQ ID 3153, SEQ ID 3156, SEQ ID 3157, SEQ ID 3158, SEQ ID 3159, SEQ ID 3160, SEQ ID 3161, SEQ ID 3162, SEQ ID 3163, SEQ ID 3164, SEQ ID 3165, SEQ ID 3166, SEQ ID 3167, SEQ ID 3168, SEQ ID 3169, SEQ ID 3170, SEQ ID 3172, SEQ ID 3173, SEQ ID 3174, SEQ ID 3175, SEQ ID 3176, SEQ ID 3177, SEQ ID 3178, SEQ ID 3179, SEQ ID 3180, SEQ ID 3181, SEQ ID 3182, SEQ ID 3183, SEQ ID 3184, SEQ ID 3186, SEQ ID 3188, SEQ ID 3191, SEQ ID 3193, SEQ ID 3196, SEQ ID 3197, SEQ ID 3203, SEQ ID 3205, SEQ ID 3206, SEQ ID 3207, SEQ ID 3210, SEQ ID 3211, SEQ ID 3212, SEQ ID 3213, SEQ ID 3214, SEQ ID 3215, SEQ ID 3216, SEQ ID 3217, SEQ ID 3218, SEQ ID 3219, SEQ ID 3221, SEQ ID 3222, SEQ ID 3223, SEQ ID 3224, SEQ ID 3227, SEQ ID 3236, SEQ ID 3237, SEQ ID 3238, SEQ ID 3239, SEQ ID 3240, SEQ ID 3241, SEQ ID 3242, SEQ ID 3243, SEQ ID 3244, SEQ ID 3245, SEQ ID 3246, SEQ ID 3248, SEQ ID 3249, SEQ ID 3250, SEQ ID 3251, SEQ ID 3252, SEQ ID 3254, SEQ ID 3258, SEQ ID 3259, SEQ ID 3261, SEQ ID 3263, SEQ ID 3265, SEQ ID 3266, SEQ ID 3267, SEQ ID 3271, SEQ ID 3272, SEQ ID 3273, SEQ ID 3276, SEQ ID 3277, SEQ ID 3279, SEQ ID 3286, SEQ ID 3295, SEQ ID 3297, SEQ ID 3305, SEQ ID 3307, SEQ ID 3309, SEQ ID 3312, SEQ ID 3313, SEQ ID 3314, SEQ ID 3316, SEQ ID 3317, SEQ ID 3318, SEQ ID 3320, SEQ ID 3332, SEQ ID 3335, SEQ ID 3336, SEQ ID 3337, SEQ ID 3338, SEQ ID 3339, SEQ ID 3340, SEQ ID 3342, SEQ ID 3343, SEQ ID 3345, SEQ ID 3346, SEQ ID 3347, SEQ ID 3348, SEQ ID 3349, SEQ ID 3350, SEQ ID 3351, SEQ ID 3352, SEQ ID 3353, SEQ ID 3354, SEQ ID 3355, SEQ ID 3356, SEQ ID 3359, SEQ ID 3360, SEQ ID 3361, SEQ ID 3362, SEQ ID 3363, SEQ ID 3364, SEQ ID 3365, SEQ ID 3366, SEQ ID 3369, SEQ ID 3370, SEQ ID 3390, SEQ ID 3392, SEQ ID 3393, SEQ ID 3394, SEQ ID 3395, SEQ ID 3396, SEQ ID 3397, SEQ ID 3398, SEQ ID 3399, SEQ ID 3401, SEQ ID 3403, SEQ ID 3404, SEQ ID 3407, SEQ ID 3408, SEQ ID 3409, SEQ ID 3410, SEQ ID 3411, SEQ ID 3412, SEQ ID 3413, SEQ ID 3414, SEQ ID 3415, SEQ ID 3417, SEQ ID 3419, SEQ ID 3420, SEQ ID 3422, SEQ ID 3423, SEQ ID 3424, SEQ ID 3428, SEQ ID 3429, SEQ ID 3430, SEQ ID 3432, SEQ ID 3433, SEQ ID 3434, SEQ ID 3435, SEQ ID 3436, SEQ ID 3437, SEQ ID 3439, SEQ ID 3440, SEQ ID 3441, SEQ ID 3442, SEQ ID 3443, SEQ ID 3444, SEQ ID 3445, SEQ ID 3446, SEQ ID 3447, SEQ ID 3448, SEQ ID 3449, SEQ ID 3450, SEQ ID 3451, SEQ ID 3452, SEQ ID 3460, SEQ ID 3461, SEQ ID 3466, SEQ ID 3467, SEQ ID 3468, SEQ ID 3490, SEQ ID 3494, SEQ ID 3496, SEQ ID 3501, SEQ ID 3505, SEQ ID 3511, SEQ ID 3512, SEQ ID 3516, SEQ ID 3517, SEQ ID 3521, SEQ ID 3522, SEQ ID 3556, SEQ ID 3557, SEQ ID 3561, SEQ ID 3566, SEQ ID 3567, SEQ ID 3568, SEQ ID 3569, SEQ ID 3571, SEQ ID 3572, SEQ ID 3576, SEQ ID 3578, SEQ ID 3580, SEQ ID 3584, SEQ ID 3594, SEQ ID 3613, SEQ ID 3614, SEQ ID 3624, SEQ ID 3625, SEQ ID 3626, SEQ ID 3627, SEQ ID 3628, SEQ ID 3633, SEQ ID 3641, SEQ ID 3643, SEQ ID 3648, SEQ ID 3651, SEQ ID 3654, SEQ ID 3656, SEQ ID 3659, SEQ ID 3660, SEQ ID 3661, SEQ ID 3670, SEQ ID 3676, SEQ ID 3680, SEQ ID 3681, SEQ ID 3683, SEQ ID 3684, SEQ ID 3685, SEQ ID 3686, SEQ ID 3687, SEQ ID 3688, SEQ ID 3689, SEQ ID 3691, SEQ ID 3693, SEQ ID 3694, SEQ ID 3695, SEQ ID 3696, SEQ ID 3698, SEQ ID 3700, SEQ ID 3701, SEQ ID 3703, SEQ ID 3704, SEQ ID 3707, SEQ ID 3708, SEQ ID 3709, SEQ ID 3710, SEQ ID 3711, SEQ ID 3712, SEQ ID 3713, SEQ ID 3714, SEQ ID 3715, SEQ ID 3716, SEQ ID 3717, SEQ ID 3718, SEQ ID 3719, SEQ ID 3720, SEQ ID 3721, SEQ ID 3722, SEQ ID 3723, SEQ ID 3725, SEQ ID 3744, SEQ ID 3747, SEQ ID 3748, SEQ ID 3749, SEQ ID 3750, SEQ ID 3751, SEQ ID 3752, SEQ ID 3753, SEQ ID 3754, SEQ ID 3755, SEQ ID 3774, SEQ ID 3775, SEQ ID 3776, SEQ ID 3786, SEQ ID 3788, SEQ ID 3790, SEQ ID 3791, SEQ ID 3793, SEQ ID 3794, SEQ ID 3795, SEQ ID 3796, SEQ ID 3797, SEQ ID 3798, SEQ ID 3799, SEQ ID 3800, SEQ ID 3801, SEQ ID 3802, SEQ ID 3803, SEQ ID 3804, SEQ ID 3805, SEQ ID 3809, SEQ ID 3810, SEQ ID 3811, SEQ ID 3812, SEQ ID 3813, SEQ ID 3814, SEQ ID 3815, SEQ ID 3821, SEQ ID 3822, SEQ ID 3823, SEQ ID 3824, SEQ ID 3825, SEQ ID 3826, SEQ ID 3827, SEQ ID 3828, SEQ ID 3830, SEQ ID 3831, SEQ ID 3832, SEQ ID 3834, SEQ ID 3836, SEQ ID 3837, SEQ ID 3838, SEQ ID 3839, SEQ ID 3840, SEQ ID 3841, SEQ ID 3842, SEQ ID 3844, SEQ ID 3850, SEQ ID 3852, SEQ ID 3867, SEQ ID 3868, SEQ ID 3870, SEQ ID 3871, SEQ ID 3872, SEQ ID 3873, SEQ ID 3874, SEQ ID 3875, SEQ ID 3876, SEQ ID 3879, SEQ ID 3880, SEQ ID 3881, SEQ ID 3882, SEQ ID 3883, SEQ ID 3884, SEQ ID 3885, SEQ ID 3886, SEQ ID 3887, SEQ ID 3888, SEQ ID 3889, SEQ ID 3890, SEQ ID 3891, SEQ ID 3892, SEQ ID 3893, SEQ ID 3894, SEQ ID 3895, SEQ ID 3896, SEQ ID 3897, SEQ ID 3908, SEQ ID 3909, SEQ ID 3910, SEQ ID 3911, SEQ ID 3912, SEQ ID 3913, SEQ ID 3922, SEQ ID 3923, SEQ ID 3930, SEQ ID 3935, SEQ ID 3936, SEQ ID 3937, SEQ ID 3938, SEQ ID 3939, SEQ ID 3940, SEQ ID 3944, SEQ ID 3945, SEQ ID 3946, SEQ ID 3947, and SEQ ID 3948.
25. The antisense oligonucleotide progranulin agonist according to any one of claims 22-24, wherein the antisense oligonucleotide progranulin agonist is selected from the group consisting of SEQ ID NOs 693-2039.
26. The antisense oligonucleotide progranulin agonist according to any one of claims 22-25, wherein the antisense oligonucleotide progranulin agonist is selected from the group consisting of SEQ ID 693, SEQ ID 694, SEQ ID 696, SEQ ID 700, SEQ ID 701, SEQ ID 703, SEQ ID 706, SEQ ID 707, SEQ ID 708, SEQ ID 709, SEQ ID 710, SEQ ID 711, SEQ ID 712, SEQ ID 713, SEQ ID 714, SEQ ID 717, SEQ ID 718, SEQ ID 719, SEQ ID 720, SEQ ID 721, SEQ ID 722, SEQ ID 723, SEQ ID 724, SEQ ID 725, SEQ ID 726, SEQ ID 727, SEQ ID 728, SEQ ID 729, SEQ ID 730, SEQ ID 731, SEQ ID 732, SEQ ID 733, SEQ ID 734, SEQ ID 736, SEQ ID 737, SEQ ID 738, SEQ ID 739, SEQ ID 740, SEQ ID 741, SEQ ID 742, SEQ ID 743, SEQ ID 744, SEQ ID 745, SEQ ID 746, SEQ ID 747, SEQ ID 748, SEQ ID 749, SEQ ID 750, SEQ ID 751, SEQ ID 752, SEQ ID 753, SEQ ID 756, SEQ ID 758, SEQ ID 759, SEQ ID 760, SEQ ID 761, SEQ ID 762, SEQ ID 764, SEQ ID 765, SEQ ID 766, SEQ ID 767, SEQ ID 768, SEQ ID 769, SEQ ID 770, SEQ ID 771, SEQ ID 772, SEQ ID 773, SEQ ID 775, SEQ ID 776, SEQ ID 777, SEQ ID 778, SEQ ID 779, SEQ ID 780, SEQ ID 782, SEQ ID 783, SEQ ID 785, SEQ ID 786, SEQ ID 787, SEQ ID 788, SEQ ID 790, SEQ ID 791, SEQ ID 793, SEQ ID 796, SEQ ID 797, SEQ ID 798, SEQ ID 799, SEQ ID 800, SEQ ID 801, SEQ ID 802, SEQ ID 803, SEQ ID 804, SEQ ID 805, SEQ ID 806, SEQ ID 807, SEQ ID 808, SEQ ID 809, SEQ ID 810, SEQ ID 811, SEQ ID 812, SEQ ID 813, SEQ ID 814, SEQ ID 815, SEQ ID 816, SEQ ID 817, SEQ ID 818, SEQ ID 819, SEQ ID 820, SEQ ID 821, SEQ ID 822, SEQ ID 823, SEQ ID 824, SEQ ID 825, SEQ ID 826, SEQ ID 827, SEQ ID 828, SEQ ID 829, SEQ ID 830, SEQ ID 831, SEQ ID 832, SEQ ID 833, SEQ ID 834, SEQ ID 835, SEQ ID 836, SEQ ID 837, SEQ ID 838, SEQ ID 839, SEQ ID 840, SEQ ID 841, SEQ ID 842, SEQ ID 843, SEQ ID 844, SEQ ID 845, SEQ ID 846, SEQ ID 847, SEQ ID 848, SEQ ID 849, SEQ ID 850, SEQ ID 851, SEQ ID 853, SEQ ID 854, SEQ ID 855, SEQ ID 856, SEQ ID 857, SEQ ID 859, SEQ ID 861, SEQ ID 862, SEQ ID 863, SEQ ID 864, SEQ ID 865, SEQ ID 866, SEQ ID 867, SEQ ID 868, SEQ ID 869, SEQ ID 870, SEQ ID 871, SEQ ID 873, SEQ ID 874, SEQ ID 875, SEQ ID 876, SEQ ID 877, SEQ ID 878, SEQ ID 879, SEQ ID 880, SEQ ID 881, SEQ ID 882, SEQ ID 883, SEQ ID 884, SEQ ID 885, SEQ ID 886, SEQ ID 887, SEQ ID 888, SEQ ID 890, SEQ ID 891, SEQ ID 892, SEQ ID 893, SEQ ID 894, SEQ ID 895, SEQ ID 896, SEQ ID 897, SEQ ID 898, SEQ ID 899, SEQ ID 900, SEQ ID 903, SEQ ID 905, SEQ ID 906, SEQ ID 907, SEQ ID 908, SEQ ID 909, SEQ ID 910, SEQ ID 912, SEQ ID 913, SEQ ID 914, SEQ ID 916, SEQ ID 918, SEQ ID 919, SEQ ID 921, SEQ ID 922, SEQ ID 923, SEQ ID 925, SEQ ID 926, SEQ ID 927, SEQ ID 928, SEQ ID 929, SEQ ID 932, SEQ ID 933, SEQ ID 934, SEQ ID 935, SEQ ID 937, SEQ ID 938, SEQ ID 939, SEQ ID 944, SEQ ID 945, SEQ ID 946, SEQ ID 947, SEQ ID 948, SEQ ID 949, SEQ ID 950, SEQ ID 951, SEQ ID 952, SEQ ID 953, SEQ ID 954, SEQ ID 955, SEQ ID 956, SEQ ID 957, SEQ ID 958, SEQ ID 960, SEQ ID 961, SEQ ID 962, SEQ ID 963, SEQ ID 964, SEQ ID 965, SEQ ID 966, SEQ ID 967, SEQ ID 968, SEQ ID 969, SEQ ID 970, SEQ ID 971, SEQ ID 973, SEQ ID 974, SEQ ID 975, SEQ ID 976, SEQ ID 978, SEQ ID 982, SEQ ID 985, SEQ ID 986, SEQ ID 987, SEQ ID 991, SEQ ID 994, SEQ ID 995, SEQ ID 996, SEQ ID 997, SEQ ID 998, SEQ ID 999, SEQ ID 1000, SEQ ID 1001, SEQ ID 1002, SEQ ID 1003, SEQ ID 1004, SEQ ID 1005, SEQ ID 1006, SEQ ID 1007, SEQ ID 1008, SEQ ID 1009, SEQ ID 1010, SEQ ID 1011, SEQ ID 1012, SEQ ID 1013, SEQ ID 1014, SEQ ID 1015, SEQ ID 1016, SEQ ID 1017, SEQ ID 1018, SEQ ID 1019, SEQ ID 1020, SEQ ID 1021, SEQ ID 1022, SEQ ID 1023, SEQ ID 1024, SEQ ID 1025, SEQ ID 1026, SEQ ID 1027, SEQ ID 1028, SEQ ID 1030, SEQ ID 1031, SEQ ID 1032, SEQ ID 1033, SEQ ID 1034, SEQ ID 1035, SEQ ID 1036, SEQ ID 1037, SEQ ID 1038, SEQ ID 1039, SEQ ID 1040, SEQ ID 1041, SEQ ID 1042, SEQ ID 1043, SEQ ID 1044, SEQ ID 1045, SEQ ID 1046, SEQ ID 1047, SEQ ID 1048, SEQ ID 1049, SEQ ID 1050, SEQ ID 1051, SEQ ID 1052, SEQ ID 1053, SEQ ID 1054, SEQ ID 1055, SEQ ID 1056, SEQ ID 1057, SEQ ID 1058, SEQ ID 1059, SEQ ID 1060, SEQ ID 1061, SEQ ID 1062, SEQ ID 1063, SEQ ID 1065, SEQ ID 1066, SEQ ID 1067, SEQ ID 1068, SEQ ID 1069, SEQ ID 1070, SEQ ID 1071, SEQ ID 1072, SEQ ID 1073, SEQ ID 1074, SEQ ID 1075, SEQ ID 1076, SEQ ID 1077, SEQ ID 1078, SEQ ID 1079, SEQ ID 1080, SEQ ID 1081, SEQ ID 1082, SEQ ID 1083, SEQ ID 1084, SEQ ID 1085, SEQ ID 1086, SEQ ID 1087, SEQ ID 1088, SEQ ID 1089, SEQ ID 1090, SEQ ID 1091, SEQ ID 1092, SEQ ID 1093, SEQ ID 1094, SEQ ID 1095, SEQ ID 1098, SEQ ID 1099, SEQ ID 1100, SEQ ID 1101, SEQ ID 1102, SEQ ID 1105, SEQ ID 1106, SEQ ID 1107, SEQ ID 1108, SEQ ID 1109, SEQ ID 1110, SEQ ID 1111, SEQ ID 1112, SEQ ID 1113, SEQ ID 1114, SEQ ID 1115, SEQ ID 1116, SEQ ID 1117, SEQ ID 1118, SEQ ID 1119, SEQ ID 1120, SEQ ID 1121, SEQ ID 1122, SEQ ID 1123, SEQ ID 1124, SEQ ID 1125, SEQ ID 1126, SEQ ID 1127, SEQ ID 1128, SEQ ID 1129, SEQ ID 1130, SEQ ID 1131, SEQ ID 1132, SEQ ID 1133, SEQ ID 1134, SEQ ID 1135, SEQ ID 1136, SEQ ID 1137, SEQ ID 1138, SEQ ID 1139, SEQ ID 1140, SEQ ID 1141, SEQ ID 1142, SEQ ID 1143, SEQ ID 1144, SEQ ID 1145, SEQ ID 1146, SEQ ID 1147, SEQ ID 1187, SEQ ID 1188, SEQ ID 1189, SEQ ID 1190, SEQ ID 1191, SEQ ID 1192, SEQ ID 1193, SEQ ID 1194, SEQ ID 1195, SEQ ID 1196, SEQ ID 1197, SEQ ID 1198, SEQ ID 1199, SEQ ID 1200, SEQ ID 1201, SEQ ID 1202, SEQ ID 1203, SEQ ID 1204, SEQ ID 1205, SEQ ID 1206, SEQ ID 1207, SEQ ID 1208, SEQ ID 1209, SEQ ID 1210, SEQ ID 1211, SEQ ID 1212, SEQ ID 1213, SEQ ID 1214, SEQ ID 1215, SEQ ID 1216, SEQ ID 1217, SEQ ID 1219, SEQ ID 1220, SEQ ID 1221, SEQ ID 1222, SEQ ID 1223, SEQ ID 1224, SEQ ID 1225, SEQ ID 1226, SEQ ID 1227, SEQ ID 1230, SEQ ID 1231, SEQ ID 1232, SEQ ID 1233, SEQ ID 1234, SEQ ID 1235, SEQ ID 1236, SEQ ID 1237, SEQ ID 1238, SEQ ID 1239, SEQ ID 1240, SEQ ID 1241, SEQ ID 1242, SEQ ID 1243, SEQ ID 1244, SEQ ID 1245, SEQ ID 1246, SEQ ID 1247, SEQ ID 1248, SEQ ID 1250, SEQ ID 1251, SEQ ID 1252, SEQ ID 1253, SEQ ID 1254, SEQ ID 1255, SEQ ID 1256, SEQ ID 1257, SEQ ID 1258, SEQ ID 1259, SEQ ID 1260, SEQ ID 1261, SEQ ID 1262, SEQ ID 1263, SEQ ID 1264, SEQ ID 1265, SEQ ID 1266, SEQ ID 1267, SEQ ID 1268, SEQ ID 1269, SEQ ID 1270, SEQ ID 1271, SEQ ID 1272, SEQ ID 1273, SEQ ID 1274, SEQ ID 1275, SEQ ID 1276, SEQ ID 1277, SEQ ID 1278, SEQ ID 1279, SEQ ID 1280, SEQ ID 1281, SEQ ID 1282, SEQ ID 1283, SEQ ID 1284, SEQ ID 1285, SEQ ID 1286, SEQ ID 1287, SEQ ID 1288, SEQ ID 1289, SEQ ID 1290, SEQ ID 1291, SEQ ID 1292, SEQ ID 1293, SEQ ID 1294, SEQ ID 1295, SEQ ID 1296, SEQ ID 1297, SEQ ID 1298, SEQ ID 1299, SEQ ID 1300, SEQ ID 1301, SEQ ID 1302, SEQ ID 1303, SEQ ID 1304, SEQ ID 1306, SEQ ID 1307, SEQ ID 1308, SEQ ID 1309, SEQ ID 1310, SEQ ID 1311, SEQ ID 1312, SEQ ID 1313, SEQ ID 1314, SEQ ID 1315, SEQ ID 1316, SEQ ID 1317, SEQ ID 1318, SEQ ID 1319, SEQ ID 1320, SEQ ID 1321, SEQ ID 1322, SEQ ID 1323, SEQ ID 1325, SEQ ID 1326, SEQ ID 1327, SEQ ID 1328, SEQ ID 1329, SEQ ID 1330, SEQ ID 1332, SEQ ID 1333, SEQ ID 1335, SEQ ID 1336, SEQ ID 1337, SEQ ID 1338, SEQ ID 1339, SEQ ID 1341, SEQ ID 1342, SEQ ID 1343, SEQ ID 1344, SEQ ID 1345, SEQ ID 1346, SEQ ID 1347, SEQ ID 1348, SEQ ID 1349, SEQ ID 1350, SEQ ID 1351, SEQ ID 1352, SEQ ID 1353, SEQ ID 1354, SEQ ID 1355, SEQ ID 1356, SEQ ID 1357, SEQ ID 1425, SEQ ID 1426, SEQ ID 1427, SEQ ID 1428, SEQ ID 1429, SEQ ID 1430, SEQ ID 1431, SEQ ID 1432, SEQ ID 1433, SEQ ID 1434, SEQ ID 1435, SEQ ID 1436, SEQ ID 1437, SEQ ID 1438, SEQ ID 1440, SEQ ID 1441, SEQ ID 1442, SEQ ID 1443, SEQ ID 1444, SEQ ID 1445, SEQ ID 1446, SEQ ID 1447, SEQ ID 1448, SEQ ID 1449, SEQ ID 1450, SEQ ID 1451, SEQ ID 1452, SEQ ID 1453, SEQ ID 1454, SEQ ID 1455, SEQ ID 1456, SEQ ID 1457, SEQ ID 1458, SEQ ID 1459, SEQ ID 1460, SEQ ID 1461, SEQ ID 1462, SEQ ID 1463, SEQ ID 1464, SEQ ID 1465, SEQ ID 1466, SEQ ID 1467, SEQ ID 1469, SEQ ID 1470, SEQ ID 1471, SEQ ID 1472, SEQ ID 1474, SEQ ID 1475, SEQ ID 1476, SEQ ID 1477, SEQ ID 1478, SEQ ID 1479, SEQ ID 1480, SEQ ID 1481, SEQ ID 1482, SEQ ID 1484, SEQ ID 1485, SEQ ID 1487, SEQ ID 1488, SEQ ID 1489, SEQ ID 1491, SEQ ID 1492, SEQ ID 1493, SEQ ID 1494, SEQ ID 1495, SEQ ID 1496, SEQ ID 1497, SEQ ID 1498, SEQ ID 1499, SEQ ID 1500, SEQ ID 1501, SEQ ID 1502, SEQ ID 1503, SEQ ID 1504, SEQ ID 1505, SEQ ID 1506, SEQ ID 1507, SEQ ID 1508, SEQ ID 1509, SEQ ID 1510, SEQ ID 1511, SEQ ID 1512, SEQ ID 1513, SEQ ID 1514, SEQ ID 1515, SEQ ID 1516, SEQ ID 1517, SEQ ID 1518, SEQ ID 1519, SEQ ID 1520, SEQ ID 1521, SEQ ID 1522, SEQ ID 1523, SEQ ID 1524, SEQ ID 1525, SEQ ID 1526, SEQ ID 1527, SEQ ID 1528, SEQ ID 1529, SEQ ID 1530, SEQ ID 1531, SEQ ID 1532, SEQ ID 1533, SEQ ID 1534, SEQ ID 1535, SEQ ID 1536, SEQ ID 1537, SEQ ID 1538, SEQ ID 1539, SEQ ID 1540, SEQ ID 1541, SEQ ID 1542, SEQ ID 1543, SEQ ID 1544, SEQ ID 1545, SEQ ID 1546, SEQ ID 1547, SEQ ID 1548, SEQ ID 1549, SEQ ID 1550, SEQ ID 1551, SEQ ID 1552, SEQ ID 1553, SEQ ID 1554, SEQ ID 1555, SEQ ID 1556, SEQ ID 1557, SEQ ID 1558, SEQ ID 1559, SEQ ID 1560, SEQ ID 1561, SEQ ID 1562, SEQ ID 1563, SEQ ID 1564, SEQ ID 1565, SEQ ID 1566, SEQ ID 1567, SEQ ID 1568, SEQ ID 1569, SEQ ID 1570, SEQ ID 1571, SEQ ID 1572, SEQ ID 1573, SEQ ID 1574, SEQ ID 1575, SEQ ID 1576, SEQ ID 1577, SEQ ID 1578, SEQ ID 1579, SEQ ID 1580, SEQ ID 1581, SEQ ID 1582, SEQ ID 1583, SEQ ID 1584, SEQ ID 1585, SEQ ID 1586, SEQ ID 1587, SEQ ID 1588, SEQ ID 1589, SEQ ID 1590, SEQ ID 1591, SEQ ID 1592, SEQ ID 1593, SEQ ID 1594, SEQ ID 1595, SEQ ID 1596, SEQ ID 1597, SEQ ID 1598, SEQ ID 1599, SEQ ID 1600, SEQ ID 1601, SEQ ID 1602, SEQ ID 1603, SEQ ID 1604, SEQ ID 1605, SEQ ID 1606, SEQ ID 1607, SEQ ID 1608, SEQ ID 1609, SEQ ID 1610, SEQ ID 1611, SEQ ID 1612, SEQ ID 1613, SEQ ID 1614, SEQ ID 1615, SEQ ID 1616, SEQ ID 1617, SEQ ID 1618, SEQ ID 1620, SEQ ID 1621, SEQ ID 1622, SEQ ID 1623, SEQ ID 1624, SEQ ID 1625, SEQ ID 1626, SEQ ID 1627, SEQ ID 1628, SEQ ID 1629, SEQ ID 1630, SEQ ID 1631, SEQ ID 1632, SEQ ID 1633, SEQ ID 1634, SEQ ID 1635, SEQ ID 1636, SEQ ID 1637, SEQ ID 1638, SEQ ID 1639, SEQ ID 1640, SEQ ID 1641, SEQ ID 1642, SEQ ID 1643, SEQ ID 1644, SEQ ID 1645, SEQ ID 1647, SEQ ID 1648, SEQ ID 1649, SEQ ID 1650, SEQ ID 1651, SEQ ID 1652, SEQ ID 1654, SEQ ID 1656, SEQ ID 1657, SEQ ID 1658, SEQ ID 1659, SEQ ID 1660, SEQ ID 1661, SEQ ID 1663, SEQ ID 1664, SEQ ID 1665, SEQ ID 1666, SEQ ID 1667, SEQ ID 1668, SEQ ID 1669, SEQ ID 1670, SEQ ID 1671, SEQ ID 1672, SEQ ID 1673, SEQ ID 1674, SEQ ID 1675, SEQ ID 1676, SEQ ID 1677, SEQ ID 1678, SEQ ID 1679, SEQ ID 1680, SEQ ID 1681, SEQ ID 1682, SEQ ID 1683, SEQ ID 1684, SEQ ID 1685, SEQ ID 1686, SEQ ID 1687, SEQ ID 1688, SEQ ID 1689, SEQ ID 1690, SEQ ID 1692, SEQ ID 1693, SEQ ID 1694, SEQ ID 1695, SEQ ID 1696, SEQ ID 1697, SEQ ID 1698, SEQ ID 1699, SEQ ID 1701, SEQ ID 1703, SEQ ID 1704, SEQ ID 1705, SEQ ID 1706, SEQ ID 1707, SEQ ID 1708, SEQ ID 1709, SEQ ID 1710, SEQ ID 1711, SEQ ID 1712, SEQ ID 1714, SEQ ID 1715, SEQ ID 1716, SEQ ID 1717, SEQ ID 1718, SEQ ID 1719, SEQ ID 1720, SEQ ID 1721, SEQ ID 1722, SEQ ID 1723, SEQ ID 1724, SEQ ID 1725, SEQ ID 1726, SEQ ID 1727, SEQ ID 1728, SEQ ID 1729, SEQ ID 1730, SEQ ID 1731, SEQ ID 1732, SEQ ID 1733, SEQ ID 1734, SEQ ID 1735, SEQ ID 1736, SEQ ID 1737, SEQ ID 1738, SEQ ID 1739, SEQ ID 1740, SEQ ID 1741, SEQ ID 1742, SEQ ID 1743, SEQ ID 1762, SEQ ID 1763, SEQ ID 1764, SEQ ID 1765, SEQ ID 1766, SEQ ID 1767, SEQ ID 1768, SEQ ID 1769, SEQ ID 1770, SEQ ID 1771, SEQ ID 1772, SEQ ID 1773, SEQ ID 1774, SEQ ID 1775, SEQ ID 1776, SEQ ID 1777, SEQ ID 1778, SEQ ID 1779, SEQ ID 1780, SEQ ID 1781, SEQ ID 1782, SEQ ID 1783, SEQ ID 1784, SEQ ID 1785, SEQ ID 1786, SEQ ID 1787, SEQ ID 1788, SEQ ID 1789, SEQ ID 1790, SEQ ID 1791, SEQ ID 1792, SEQ ID 1793, SEQ ID 1794, SEQ ID 1795, SEQ ID 1796, SEQ ID 1797, SEQ ID 1798, SEQ ID 1799, SEQ ID 1800, SEQ ID 1801, SEQ ID 1802, SEQ ID 1803, SEQ ID 1804, SEQ ID 1805, SEQ ID 1806, SEQ ID 1807, SEQ ID 1808, SEQ ID 1809, SEQ ID 1810, SEQ ID 1811, SEQ ID 1812, SEQ ID 1813, SEQ ID 1814, SEQ ID 1815, SEQ ID 1816, SEQ ID 1817, SEQ ID 1818, SEQ ID 1819, SEQ ID 1820, SEQ ID 1821, SEQ ID 1822, SEQ ID 1823, SEQ ID 1824, SEQ ID 1825, SEQ ID 1826, SEQ ID 1832, SEQ ID 1833, SEQ ID 1836, SEQ ID 1837, SEQ ID 1838, SEQ ID 1839, SEQ ID 1840, SEQ ID 1858, SEQ ID 1859, SEQ ID 1860, SEQ ID 1861, SEQ ID 1862, SEQ ID 1863, SEQ ID 1865, SEQ ID 1866, SEQ ID 1868, SEQ ID 1869, SEQ ID 1873, SEQ ID 1877, SEQ ID 1880, SEQ ID 1883, SEQ ID 1884, SEQ ID 1888, SEQ ID 1889, SEQ ID 1890, SEQ ID 1893, SEQ ID 1894, SEQ ID 1895, SEQ ID 1896, SEQ ID 1897, SEQ ID 1898, SEQ ID 1899, SEQ ID 1900, SEQ ID 1902, SEQ ID 1903, SEQ ID 1904, SEQ ID 1906, SEQ ID 1907, SEQ ID 1908, SEQ ID 1910, SEQ ID 1911, SEQ ID 1913, SEQ ID 1914, SEQ ID 1915, SEQ ID 1916, SEQ ID 1918, SEQ ID 1920, SEQ ID 1921, SEQ ID 1922, SEQ ID 1924, SEQ ID 1928, SEQ ID 1929, SEQ ID 1930, SEQ ID 1932, SEQ ID 1933, SEQ ID 1938, SEQ ID 1939, SEQ ID 1940, SEQ ID 1941, SEQ ID 1943, SEQ ID 1944, SEQ ID 1945, SEQ ID 1946, SEQ ID 1948, SEQ ID 1949, SEQ ID 1950, SEQ ID 1952, SEQ ID 1953, SEQ ID 1956, SEQ ID 1957, SEQ ID 1958, SEQ ID 1960, SEQ ID 1962, SEQ ID 1964, SEQ ID 1966, SEQ ID 1967, SEQ ID 1970, SEQ ID 1971, SEQ ID 1972, SEQ ID 1973, SEQ ID 1974, SEQ ID 1975, SEQ ID 1977, SEQ ID 1979, SEQ ID 1981, SEQ ID 1982, SEQ ID 1985, SEQ ID 1986, SEQ ID 1987, SEQ ID 1988, SEQ ID 1989, SEQ ID 1993, SEQ ID 1995, SEQ ID 1996, SEQ ID 1997, SEQ ID 1998, SEQ ID 1999, SEQ ID 2000, SEQ ID 2001, SEQ ID 2002, SEQ ID 2003, SEQ ID 2004, SEQ ID 2005, SEQ ID 2008, SEQ ID 2009, SEQ ID 2010, SEQ ID 2011, SEQ ID 2013, SEQ ID 2014, SEQ ID 2015, SEQ ID 2017, SEQ ID 2019, SEQ ID 2020, SEQ ID 2021, SEQ ID 2023, SEQ ID 2026, SEQ ID 2028, SEQ ID 2031, SEQ ID 2032, SEQ ID 2033, SEQ ID 2035, SEQ ID 2036, SEQ ID 2037, SEQ ID 2038, SEQ ID 2042, SEQ ID 2044, SEQ ID 2048, SEQ ID 2050, SEQ ID 2051, SEQ ID 2052, SEQ ID 2053, SEQ ID 2054, SEQ ID 2055, SEQ ID 2056, SEQ ID 2057, SEQ ID 2058, SEQ ID 2059, SEQ ID 2060, SEQ ID 2061, SEQ ID 2062, SEQ ID 2063, SEQ ID 2064, SEQ ID 2065, SEQ ID 2066, SEQ ID 2067, SEQ ID 2068, SEQ ID 2069, SEQ ID 2070, SEQ ID 2071, SEQ ID 2072, SEQ ID 2073, SEQ ID 2074, SEQ ID 2075, SEQ ID 2076, SEQ ID 2077, SEQ ID 2078, SEQ ID 2079, SEQ ID 2080, SEQ ID 2081, SEQ ID 2082, SEQ ID 2083, SEQ ID 2084, SEQ ID 2085, SEQ ID 2086, SEQ ID 2087, SEQ ID 2088, SEQ ID 2089, SEQ ID 2090, SEQ ID 2091, SEQ ID 2092, SEQ ID 2093, SEQ ID 2094, SEQ ID 2095, SEQ ID 2096, SEQ ID 2097, SEQ ID 2098, SEQ ID 2099, SEQ ID 2101, SEQ ID 2102, SEQ ID 2103, SEQ ID 2104, SEQ ID 2105, SEQ ID 2106, SEQ ID 2107, SEQ ID 2108, SEQ ID 2109, SEQ ID 2110, SEQ ID 2111, SEQ ID 2112, SEQ ID 2113, SEQ ID 2114, SEQ ID 2115, SEQ ID 2116, SEQ ID 2117, SEQ ID 2118, SEQ ID 2119, SEQ ID 2120, SEQ ID 2121, SEQ ID 2122, SEQ ID 2123, SEQ ID 2124, SEQ ID 2125, SEQ ID 2126, SEQ ID 2127, SEQ ID 2146, SEQ ID 2147, SEQ ID 2148, SEQ ID 2149, SEQ ID 2150, SEQ ID 2151, SEQ ID 2152, SEQ ID 2153, SEQ ID 2154, SEQ ID 2155, SEQ ID 2156, SEQ ID 2157, SEQ ID 2158, SEQ ID 2159, SEQ ID 2160, SEQ ID 2161, SEQ ID 2162, SEQ ID 2163, SEQ ID 2164, SEQ ID 2165, SEQ ID 2166, SEQ ID 2167, SEQ ID 2168, SEQ ID 2169, SEQ ID 2170, SEQ ID 2171, SEQ ID 2172, SEQ ID 2173, SEQ ID 2174, SEQ ID 2175, SEQ ID 2176, SEQ ID 2177, SEQ ID 2178, SEQ ID 2179, SEQ ID 2180, SEQ ID 2181, SEQ ID 2182, SEQ ID 2183, SEQ ID 2184, SEQ ID 2185, SEQ ID 2186, SEQ ID 2187, SEQ ID 2188, SEQ ID 2189, SEQ ID 2190, SEQ ID 2191, SEQ ID 2192, SEQ ID 2193, SEQ ID 2194, SEQ ID 2195, SEQ ID 2196, SEQ ID 2197, SEQ ID 2198, SEQ ID 2199, SEQ ID 2200, SEQ ID 2201, SEQ ID 2202, SEQ ID 2203, SEQ ID 2204, SEQ ID 2205, SEQ ID 2206, SEQ ID 2207, SEQ ID 2208, SEQ ID 2209, SEQ ID 2210, SEQ ID 2211, SEQ ID 2212, SEQ ID 2213, SEQ ID 2214, SEQ ID 2216, SEQ ID 2220, SEQ ID 2222, SEQ ID 2223, SEQ ID 2224, SEQ ID 2225, SEQ ID 2239, SEQ ID 2240, SEQ ID 2241, SEQ ID 2242, SEQ ID 2243, SEQ ID 2244, SEQ ID 2245, SEQ ID 2246, SEQ ID 2247, SEQ ID 2248, SEQ ID 2249, SEQ ID 2250, SEQ ID 2251, SEQ ID 2252, SEQ ID 2253, SEQ ID 2254, SEQ ID 2255, SEQ ID 2256, SEQ ID 2257, SEQ ID 2258, SEQ ID 2259, SEQ ID 2260, SEQ ID 2261, SEQ ID 2262, SEQ ID 2263, SEQ ID 2264, SEQ ID 2265, SEQ ID 2266, SEQ ID 2267, SEQ ID 2268, SEQ ID 2269, SEQ ID 2270, SEQ ID 2271, SEQ ID 2272, SEQ ID 2273, SEQ ID 2274, SEQ ID 2275, SEQ ID 2276, SEQ ID 2277, SEQ ID 2278, SEQ ID 2279, SEQ ID 2280, SEQ ID 2281, SEQ ID 2282, SEQ ID 2283, SEQ ID 2284, SEQ ID 2285, SEQ ID 2286, SEQ ID 2287, SEQ ID 2288, SEQ ID 2289, SEQ ID 2290, SEQ ID 2291, SEQ ID 2292, SEQ ID 2293, SEQ ID 2294, SEQ ID 2295, SEQ ID 2296, SEQ ID 2297, SEQ ID 2298, SEQ ID 2299, SEQ ID 2300, SEQ ID 2301, SEQ ID 2302, SEQ ID 2303, SEQ ID 2304, SEQ ID 2305, SEQ ID 2306, SEQ ID 2307, SEQ ID 2308, SEQ ID 2309, SEQ ID 2310, SEQ ID 2311, SEQ ID 2312, SEQ ID 2313, SEQ ID 2314, SEQ ID 2315, SEQ ID 2316, SEQ ID 2317, SEQ ID 2318, SEQ ID 2319, and SEQ ID 2320.
27. The antisense oligonucleotide progranulin agonist according to any one of claims 22-26, wherein the antisense oligonucleotide progranulin agonist is selected from the group consisting of SEQ ID 693, SEQ ID 707, SEQ ID 708, SEQ ID 709, SEQ ID 710, SEQ ID 711, SEQ ID 720, SEQ ID 721, SEQ ID 723, SEQ ID 724, SEQ ID 725, SEQ ID 726, SEQ ID 727, SEQ ID 730, SEQ ID 732, SEQ ID 736, SEQ ID 737, SEQ ID 738, SEQ ID 739, SEQ ID 741, SEQ ID 743, SEQ ID 745, SEQ ID 747, SEQ ID 758, SEQ ID 759, SEQ ID 760, SEQ ID 761, SEQ ID 766, SEQ ID 775, SEQ ID 798, SEQ ID 800, SEQ ID 801, SEQ ID 802, SEQ ID 803, SEQ ID 804, SEQ ID 807, SEQ ID 812, SEQ ID 813, SEQ ID 814, SEQ ID 816, SEQ ID 818, SEQ ID 819, SEQ ID 822, SEQ ID 823, SEQ ID 824, SEQ ID 825, SEQ ID 826, SEQ ID 827, SEQ ID 828, SEQ ID 830, SEQ ID 831, SEQ ID 833, SEQ ID 835, SEQ ID 836, SEQ ID 837, SEQ ID 838, SEQ ID 839, SEQ ID 840, SEQ ID 841, SEQ ID 842, SEQ ID 843, SEQ ID 844, SEQ ID 845, SEQ ID 846, SEQ ID 847, SEQ ID 848, SEQ ID 849, SEQ ID 850, SEQ ID 854, SEQ ID 855, SEQ ID 856, SEQ ID 857, SEQ ID 859, SEQ ID 861, SEQ ID 866, SEQ ID 867, SEQ ID 868, SEQ ID 869, SEQ ID 871, SEQ ID 873, SEQ ID 874, SEQ ID 876, SEQ ID 878, SEQ ID 879, SEQ ID 880, SEQ ID 881, SEQ ID 883, SEQ ID 885, SEQ ID 887, SEQ ID 888, SEQ ID 890, SEQ ID 891, SEQ ID 892, SEQ ID 893, SEQ ID 895, SEQ ID 897, SEQ ID 906, SEQ ID 909, SEQ ID 916, SEQ ID 918, SEQ ID 926, SEQ ID 927, SEQ ID 928, SEQ ID 932, SEQ ID 933, SEQ ID 934, SEQ ID 967, SEQ ID 998, SEQ ID 1000, SEQ ID 1001, SEQ ID 1002, SEQ ID 1003, SEQ ID 1005, SEQ ID 1010, SEQ ID 1011, SEQ ID 1012, SEQ ID 1021, SEQ ID 1023, SEQ ID 1024, SEQ ID 1027, SEQ ID 1030, SEQ ID 1037, SEQ ID 1038, SEQ ID 1039, SEQ ID 1041, SEQ ID 1042, SEQ ID 1048, SEQ ID 1049, SEQ ID 1050, SEQ ID 1051, SEQ ID 1054, SEQ ID 1058, SEQ ID 1060, SEQ ID 1061, SEQ ID 1063, SEQ ID 1066, SEQ ID 1070, SEQ ID 1071, SEQ ID 1072, SEQ ID 1073, SEQ ID 1075, SEQ ID 1078, SEQ ID 1081, SEQ ID 1083, SEQ ID 1084, SEQ ID 1085, SEQ ID 1086, SEQ ID 1091, SEQ ID 1092, SEQ ID 1093, SEQ ID 1109, SEQ ID 1111, SEQ ID 1112, SEQ ID 1113, SEQ ID 1114, SEQ ID 1115, SEQ ID 1116, SEQ ID 1117, SEQ ID 1118, SEQ ID 1119, SEQ ID 1120, SEQ ID 1121, SEQ ID 1122, SEQ ID 1123, SEQ ID 1124, SEQ ID 1125, SEQ ID 1126, SEQ ID 1127, SEQ ID 1128, SEQ ID 1129, SEQ ID 1130, SEQ ID 1132, SEQ ID 1135, SEQ ID 1136, SEQ ID 1137, SEQ ID 1138, SEQ ID 1139, SEQ ID 1140, SEQ ID 1141, SEQ ID 1142, SEQ ID 1143, SEQ ID 1144, SEQ ID 1146, SEQ ID 1188, SEQ ID 1189, SEQ ID 1190, SEQ ID 1191, SEQ ID 1192, SEQ ID 1196, SEQ ID 1200, SEQ ID 1201, SEQ ID 1202, SEQ ID 1203, SEQ ID 1204, SEQ ID 1205, SEQ ID 1206, SEQ ID 1207, SEQ ID 1208, SEQ ID 1209, SEQ ID 1223, SEQ ID 1224, SEQ ID 1238, SEQ ID 1243, SEQ ID 1244, SEQ ID 1258, SEQ ID 1259, SEQ ID 1262, SEQ ID 1263, SEQ ID 1264, SEQ ID 1267, SEQ ID 1268, SEQ ID 1271, SEQ ID 1276, SEQ ID 1282, SEQ ID 1283, SEQ ID 1284, SEQ ID 1285, SEQ ID 1286, SEQ ID 1288, SEQ ID 1290, SEQ ID 1291, SEQ ID 1292, SEQ ID 1294, SEQ ID 1297, SEQ ID 1298, SEQ ID 1304, SEQ ID 1311, SEQ ID 1313, SEQ ID 1314, SEQ ID 1315, SEQ ID 1344, SEQ ID 1345, SEQ ID 1346, SEQ ID 1347, SEQ ID 1348, SEQ ID 1349, SEQ ID 1352, SEQ ID 1355, SEQ ID 1357, SEQ ID 1425, SEQ ID 1426, SEQ ID 1427, SEQ ID 1428, SEQ ID 1430, SEQ ID 1431, SEQ ID 1432, SEQ ID 1433, SEQ ID 1434, SEQ ID 1435, SEQ ID 1436, SEQ ID 1437, SEQ ID 1438, SEQ ID 1440, SEQ ID 1441, SEQ ID 1442, SEQ ID 1443, SEQ ID 1444, SEQ ID 1445, SEQ ID 1446, SEQ ID 1447, SEQ ID 1448, SEQ ID 1449, SEQ ID 1450, SEQ ID 1451, SEQ ID 1454, SEQ ID 1455, SEQ ID 1456, SEQ ID 1457, SEQ ID 1460, SEQ ID 1461, SEQ ID 1462, SEQ ID 1463, SEQ ID 1464, SEQ ID 1467, SEQ ID 1469, SEQ ID 1474, SEQ ID 1478, SEQ ID 1480, SEQ ID 1482, SEQ ID 1488, SEQ ID 1492, SEQ ID 1493, SEQ ID 1497, SEQ ID 1498, SEQ ID 1505, SEQ ID 1506, SEQ ID 1507, SEQ ID 1509, SEQ ID 1510, SEQ ID 1512, SEQ ID 1513, SEQ ID 1514, SEQ ID 1515, SEQ ID 1517, SEQ ID 1520, SEQ ID 1524, SEQ ID 1525, SEQ ID 1528, SEQ ID 1529, SEQ ID 1530, SEQ ID 1531, SEQ ID 1532, SEQ ID 1533, SEQ ID 1534, SEQ ID 1535, SEQ ID 1536, SEQ ID 1537, SEQ ID 1538, SEQ ID 1539, SEQ ID 1540, SEQ ID 1541, SEQ ID 1542, SEQ ID 1544, SEQ ID 1545, SEQ ID 1546, SEQ ID 1547, SEQ ID 1548, SEQ ID 1549, SEQ ID 1550, SEQ ID 1551, SEQ ID 1552, SEQ ID 1553, SEQ ID 1554, SEQ ID 1555, SEQ ID 1556, SEQ ID 1558, SEQ ID 1560, SEQ ID 1563, SEQ ID 1565, SEQ ID 1568, SEQ ID 1569, SEQ ID 1575, SEQ ID 1577, SEQ ID 1578, SEQ ID 1579, SEQ ID 1582, SEQ ID 1583, SEQ ID 1584, SEQ ID 1585, SEQ ID 1586, SEQ ID 1587, SEQ ID 1588, SEQ ID 1589, SEQ ID 1590, SEQ ID 1591, SEQ ID 1593, SEQ ID 1594, SEQ ID 1595, SEQ ID 1596, SEQ ID 1599, SEQ ID 1608, SEQ ID 1609, SEQ ID 1610, SEQ ID 1611, SEQ ID 1612, SEQ ID 1613, SEQ ID 1614, SEQ ID 1615, SEQ ID 1616, SEQ ID 1617, SEQ ID 1618, SEQ ID 1620, SEQ ID 1621, SEQ ID 1622, SEQ ID 1623, SEQ ID 1624, SEQ ID 1626, SEQ ID 1630, SEQ ID 1631, SEQ ID 1633, SEQ ID 1635, SEQ ID 1637, SEQ ID 1638, SEQ ID 1639, SEQ ID 1643, SEQ ID 1644, SEQ ID 1645, SEQ ID 1648, SEQ ID 1649, SEQ ID 1651, SEQ ID 1658, SEQ ID 1667, SEQ ID 1669, SEQ ID 1677, SEQ ID 1679, SEQ ID 1681, SEQ ID 1684, SEQ ID 1685, SEQ ID 1686, SEQ ID 1688, SEQ ID 1689, SEQ ID 1690, SEQ ID 1692, SEQ ID 1704, SEQ ID 1707, SEQ ID 1708, SEQ ID 1709, SEQ ID 1710, SEQ ID 1711, SEQ ID 1712, SEQ ID 1714, SEQ ID 1715, SEQ ID 1717, SEQ ID 1718, SEQ ID 1719, SEQ ID 1720, SEQ ID 1721, SEQ ID 1722, SEQ ID 1723, SEQ ID 1724, SEQ ID 1725, SEQ ID 1726, SEQ ID 1727, SEQ ID 1728, SEQ ID 1731, SEQ ID 1732, SEQ ID 1733, SEQ ID 1734, SEQ ID 1735, SEQ ID 1736, SEQ ID 1737, SEQ ID 1738, SEQ ID 1741, SEQ ID 1742, SEQ ID 1762, SEQ ID 1764, SEQ ID 1765, SEQ ID 1766, SEQ ID 1767, SEQ ID 1768, SEQ ID 1769, SEQ ID 1770, SEQ ID 1771, SEQ ID 1773, SEQ ID 1775, SEQ ID 1776, SEQ ID 1779, SEQ ID 1780, SEQ ID 1781, SEQ ID 1782, SEQ ID 1783, SEQ ID 1784, SEQ ID 1785, SEQ ID 1786, SEQ ID 1787, SEQ ID 1789, SEQ ID 1791, SEQ ID 1792, SEQ ID 1794, SEQ ID 1795, SEQ ID 1796, SEQ ID 1800, SEQ ID 1801, SEQ ID 1802, SEQ ID 1804, SEQ ID 1805, SEQ ID 1806, SEQ ID 1807, SEQ ID 1808, SEQ ID 1809, SEQ ID 1811, SEQ ID 1812, SEQ ID 1813, SEQ ID 1814, SEQ ID 1815, SEQ ID 1816, SEQ ID 1817, SEQ ID 1818, SEQ ID 1819, SEQ ID 1820, SEQ ID 1821, SEQ ID 1822, SEQ ID 1823, SEQ ID 1824, SEQ ID 1832, SEQ ID 1833, SEQ ID 1838, SEQ ID 1839, SEQ ID 1840, SEQ ID 1862, SEQ ID 1866, SEQ ID 1868, SEQ ID 1873, SEQ ID 1877, SEQ ID 1883, SEQ ID 1884, SEQ ID 1888, SEQ ID 1889, SEQ ID 1893, SEQ ID 1894, SEQ ID 1928, SEQ ID 1929, SEQ ID 1933, SEQ ID 1938, SEQ ID 1939, SEQ ID 1940, SEQ ID 1941, SEQ ID 1943, SEQ ID 1944, SEQ ID 1948, SEQ ID 1950, SEQ ID 1952, SEQ ID 1956, SEQ ID 1966, SEQ ID 1985, SEQ ID 1986, SEQ ID 1996, SEQ ID 1997, SEQ ID 1998, SEQ ID 1999, SEQ ID 2000, SEQ ID 2005, SEQ ID 2013, SEQ ID 2015, SEQ ID 2020, SEQ ID 2023, SEQ ID 2026, SEQ ID 2028, SEQ ID 2031, SEQ ID 2032, SEQ ID 2033, SEQ ID 2042, SEQ ID 2048, SEQ ID 2052, SEQ ID 2053, SEQ ID 2055, SEQ ID 2056, SEQ ID 2057, SEQ ID 2058, SEQ ID 2059, SEQ ID 2060, SEQ ID 2061, SEQ ID 2063, SEQ ID 2065, SEQ ID 2066, SEQ ID 2067, SEQ ID 2068, SEQ ID 2070, SEQ ID 2072, SEQ ID 2073, SEQ ID 2075, SEQ ID 2076, SEQ ID 2079, SEQ ID 2080, SEQ ID 2081, SEQ ID 2082, SEQ ID 2083, SEQ ID 2084, SEQ ID 2085, SEQ ID 2086, SEQ ID 2087, SEQ ID 2088, SEQ ID 2089, SEQ ID 2090, SEQ ID 2091, SEQ ID 2092, SEQ ID 2093, SEQ ID 2094, SEQ ID 2095, SEQ ID 2097, SEQ ID 2116, SEQ ID 2119, SEQ ID 2120, SEQ ID 2121, SEQ ID 2122, SEQ ID 2123, SEQ ID 2124, SEQ ID 2125, SEQ ID 2126, SEQ ID 2127, SEQ ID 2146, SEQ ID 2147, SEQ ID 2148, SEQ ID 2158, SEQ ID 2160, SEQ ID 2162, SEQ ID 2163, SEQ ID 2165, SEQ ID 2166, SEQ ID 2167, SEQ ID 2168, SEQ ID 2169, SEQ ID 2170, SEQ ID 2171, SEQ ID 2172, SEQ ID 2173, SEQ ID 2174, SEQ ID 2175, SEQ ID 2176, SEQ ID 2177, SEQ ID 2181, SEQ ID 2182, SEQ ID 2183, SEQ ID 2184, SEQ ID 2185, SEQ ID 2186, SEQ ID 2187, SEQ ID 2193, SEQ ID 2194, SEQ ID 2195, SEQ ID 2196, SEQ ID 2197, SEQ ID 2198, SEQ ID 2199, SEQ ID 2200, SEQ ID 2202, SEQ ID 2203, SEQ ID 2204, SEQ ID 2206, SEQ ID 2208, SEQ ID 2209, SEQ ID 2210, SEQ ID 2211, SEQ ID 2212, SEQ ID 2213, SEQ ID 2214, SEQ ID 2216, SEQ ID 2222, SEQ ID 2224, SEQ ID 2239, SEQ ID 2240, SEQ ID 2242, SEQ ID 2243, SEQ ID 2244, SEQ ID 2245, SEQ ID 2246, SEQ ID 2247, SEQ ID 2248, SEQ ID 2251, SEQ ID 2252, SEQ ID 2253, SEQ ID 2254, SEQ ID 2255, SEQ ID 2256, SEQ ID 2257, SEQ ID 2258, SEQ ID 2259, SEQ ID 2260, SEQ ID 2261, SEQ ID 2262, SEQ ID 2263, SEQ ID 2264, SEQ ID 2265, SEQ ID 2266, SEQ ID 2267, SEQ ID 2268, SEQ ID 2269, SEQ ID 2280, SEQ ID 2281, SEQ ID 2282, SEQ ID 2283, SEQ ID 2284, SEQ ID 2285, SEQ ID 2294, SEQ ID 2295, SEQ ID 2302, SEQ ID 2307, SEQ ID 2308, SEQ ID 2309, SEQ ID 2310, SEQ ID 2311, SEQ ID 2312, SEQ ID 2316, SEQ ID 2317, SEQ ID 2318, SEQ ID 2319, and SEQ ID 2320.
28. The antisense oligonucleotide progranulin agonist according to any one of claims 1-20, wherein the antisense oligonucleotide progranulin agonist is or comprises an antisense oligonucleotide mixmer or totalmer.
29. The antisense oligonucleotide progranulin agonist of any one of claims 1-28, wherein the antisense oligonucleotide progranulin agonist or contiguous nucleotide sequence thereof is 10-20 nucleotides in length.
30. An antisense oligonucleotide progranulin agonist having the structure:
31. An antisense oligonucleotide progranulin agonist wherein the oligonucleotide is the oligonucleotide compound TgGccAggGatCagGG (SEQ ID NO: 106) wherein capital letters represent beta-D-oxy LNA nucleosides, lowercase letters represent DNA nucleosides, all LNA C are 5-methyl cytosine, and all internucleoside linkages are phosphorothioate internucleoside linkages.
32. An antisense oligonucleotide progranulin agonist according to any one of claims 1-31 covalently attached to at least one conjugate moiety.
33. An antisense oligonucleotide progranulin agonist according to any one of claims 1-32 wherein the antisense oligonucleotide progranulin agonist is in the form of a pharmaceutically acceptable salt.
34. An antisense oligonucleotide progranulin agonist according to claim 33 wherein the salt is a sodium salt or a potassium salt.
35. A pharmaceutical composition comprising the antisense oligonucleotide progranulin agonist according to any one of claims 1-34 and a pharmaceutically acceptable diluent, solvent, carrier, salt and/or adjuvant.
36. A pharmaceutical composition according to claim 35, wherein the pharmaceutical composition comprises an aqueous diluent or solvent, such as phosphate buffered saline.
37. An in vivo or in vitro method for enhancing the expression of progranulin in a cell which is expressing progranulin, said method comprising administering an antisense oligonucleotide progranulin agonist according to any one of claims 1-34, or the pharmaceutical composition according to claim 35 or claim 36 in an effective amount to said cell.
38. The method according to claim 37, wherein the cell is either a human cell or a mammalian cell.
39. A method for treating or preventing neurological disease comprising administering a therapeutically or prophylactically effective amount of an antisense oligonucleotide progranulin agonist according to any one of claims 1-34 or the pharmaceutical composition according to claim 35 or claim 365 to a subject suffering from or susceptible to neurological disease.
40. The antisense oligonucleotide progranulin agonist according to any one of claims 1-34, or the pharmaceutical composition according to claim 35 or claim 36 for use as a medicament.
41. The antisense oligonucleotide progranulin agonist according to any one of claims 1-33, or the pharmaceutical composition according to claim 35 or claim 36 for use in the treatment of a neurological disease.
42. The antisense oligonucleotide progranulin agonist or pharmaceutical composition for use in the treatment of a neurological disease according to claim 41, wherein the neurological disease is a TDP-43 pathology.
43. The antisense oligonucleotide progranulin agonist according to any one of claims 1-34 or the pharmaceutical composition according to claim 35 or claim 36 for use in the treatment of progranulin haploinsufficiency.
44. Use of the antisense oligonucleotide progranulin agonist according to claims 1-34, or the pharmaceutical composition according to claim 35 or claim 36 for the preparation of a medicament for treatment or prevention of a neurological disease.
45. Use of an antisense oligonucleotide progranulin agonist, or pharmaceutical composition according to claim 44, wherein the neurological disease is a TDP-43 pathology.
46. Use of the antisense oligonucleotide progranulin agonist according to claim 1-34, or the pharmaceutical composition according to claim 35 or claim 36, for the preparation of a medicament for treatment of progranulin haploinsufficiency.
47. The method or use according to any one of claims 37-46, wherein the method or use is for the treatment of fronto temporal dementia (FTD), neuropathologic frontotemporal lobar degeneration or neuroinflammation.

Priority Claims (2)

Number	Date	Country	Kind
20174322.6	May 2020	EP	regional
20210822.1	Nov 2020	EP	regional

Continuations (1)

	Number	Date	Country
Parent	PCT/EP2021/062785	May 2021	US
Child	17986101		US

Oligonucleotide Agonists Targeting Progranulin

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Priority Claims (2)

Continuations (1)