OVEREXPRESSION OF LEMD2, LEMD3, OR CHMP7 AS A THERAPEUTIC MODALITY FOR TAUOPATHY

Abstract

Provided herein are methods of inhibiting tau aggregation in a cell or a subject, comprising administering a LEM domain-containing protein 2 (LEMD2), a charged multivesicular body protein 7 (CHMP7), or an inner nuclear membrane protein Man 1 (LEMD3) or a nucleic acid encoding the LEMD2, the CHMP7, or the LEMD3 to the cell or the subject. Also provided herein are methods of treating or preventing a tauopathy in a subject, comprising administering LEMD2, CHMP7, or LEMD3 or a nucleic acid encoding the LEMD2, the CHMP7, or the LEMD3 to the subject, wherein the LEMD2, the CHMP7, or the LEMD3 inhibits tau aggregation in a cell in the subject. Also provided are nucleic acids encoding LEMD2, CHMP7, or LEMD3 (e.g., in an expression construct and operably linked to a heterologous promoter).

Description

Claims

1. A method of inhibiting tau aggregation in a cell, comprising administering a LEM domain-containing protein 2 (LEMD2), a charged multivesicular body protein 7 (CHMP7), or an inner nuclear membrane protein Man 1 (LEMD3) or a nucleic acid encoding the LEMD2, the CHMP7, or the LEMD3 to the cell.

2. A method of inhibiting or reducing tau phosphorylation in a cell, comprising administering a LEM domain-containing protein 2 (LEMD2), a charged multivesicular body protein 7 (CHMP7), or an inner nuclear membrane protein Man 1 (LEMD3) or a nucleic acid encoding the LEMD2, the CHMP7, or the LEMD3 to the cell.

3. (canceled)

4. (canceled)

5. A method of inhibiting or reducing accumulation of insoluble tau in a cell, comprising administering a LEM domain-containing protein 2 (LEMD2), a charged multivesicular body protein 7 (CHMP7), or an inner nuclear membrane protein Man 1 (LEMD3) or a nucleic acid encoding the LEMD2, the CHMP7, or the LEMD3 to the cell.

6. The method of claim 1, comprising administering the LEMD2 or the nucleic acid encoding the LEMD2 to the cell.

7. The method of claim 6, wherein the LEMD2 is a human LEMD2, optionally wherein the LEMD2 comprises SEQ ID NO: 1 or 5, and optionally wherein the nucleic acid encoding the LEMD2 comprises SEQ ID NO: 2, 3, 6, or 7.

8. The method of claim 6, wherein the LEMD2 is a mouse LEMD2, optionally wherein the LEMD2 comprises SEQ ID NO: 10, and optionally wherein the nucleic acid encoding the LEMD2 comprises SEQ ID NO: 11, 12, 13, or 255.

9. The method of claim 1, comprising administering the CHMP7 or the nucleic acid encoding the CHMP7 to the cell.

10. The method of claim 9, wherein the CHMP7 is a human CHMP7, optionally wherein the CHMP7 comprises SEQ ID NO: 15, and optionally wherein the nucleic acid encoding the CHMP7 comprises SEQ ID NO: 16 or 17.

11. The method of claim 9, wherein the CHMP7 is a mouse CHMP7, optionally wherein the CHMP7 comprises SEQ ID NO: 19, and optionally wherein the nucleic acid encoding the CHMP7 comprises SEQ ID NO: 20 or 21.

12. The method of claim 1, comprising administering the LEMD3 or the nucleic acid encoding the LEMD3 to the cell.

13. The method of claim 12, wherein the LEMD3 is a human LEMD3, optionally wherein the LEMD3 comprises SEQ ID NO: 23, and optionally wherein the nucleic acid encoding the LEMD3 comprises SEQ ID NO: 24 or 25.

14. The method of claim 12, wherein the LEMD3 is a mouse LEMD3, optionally wherein the LEMD3 comprises SEQ ID NO: 27 or 29, and optionally wherein the nucleic acid encoding the LEMD3 comprises SEQ ID NO: 29 or 30.

15. The method of claim 1, wherein the nucleic acid encoding the LEMD2, the CHMP7, or the LEMD3 is administered to the cell, optionally wherein the nucleic acid is codon-optimized for expression in human cells or mouse cells.

16. The method of claim 15, wherein the nucleic acid comprises a complementary DNA encoding the LEMD2, the CHMP7, or the LEMD3.

17. The method of claim 15, wherein the nucleic acid comprises a messenger RNA encoding the LEMD2, the CHMP7, or the LEMD3.

18. The method of claim 15, wherein the method comprises administering an expression construct comprising the nucleic acid encoding the LEMD2, the CHMP7, or the LEMD3 operably linked to a promoter.

19. The method of claim 18, wherein the promoter is a heterologous promoter.

20. The method of claim 18, wherein the promoter is a constitutive promoter, a tissue-specific promoter, or an inducible promoter.

21. The method of claim 20, wherein the promoter is a neuron-specific promoter.

22. The method of claim 21, wherein the promoter is a synapsin-1 promoter.

23. The method of claim 22, wherein the promoter is a human synapsin-1 promoter.

24. The method of claim 15, wherein the nucleic acid is in a vector.

25. The method of claim 24, wherein the vector is a viral vector.

26. The method of claim 25, wherein the viral vector is a lentivirus vector or an adeno-associated virus (AAV) vector.

27. The method of claim 26, wherein the vector is the AAV vector, optionally wherein the AAV vector is an AAV-PHP.eB vector.

28. The method of claim 1, wherein the cell is a mammalian cell.

29. The method of claim 28, wherein the mammalian cell is a human cell, a rodent cell, a mouse cell, or a rat cell.

30. The method of claim 29, wherein the cell is the human cell.

31. The method of claim 1, wherein the cell is a neuron.

32. The method of claim 1, wherein the cell is in vivo in a subject.

33. The method of claim 32, wherein the cell is a neuron in the brain of the subject.

34. The method of claim 32, wherein the LEMD2, the CHMP7, or the LEMD3 or the nucleic acid encoding the LEMD2, the CHMP7, or the LEMD3 is administered to the subject via intracerebroventricular injection, intracranial injection, or intrathecal injection.

35. The method of claim 1, further comprising assessing one or more signs or symptoms of tauopathy or tau aggregation in the cell.

36. The method of claim 35, further comprising assessing phospho-tau levels in the cell.

37. The method of claim 1, wherein the method reduces the amount of new tau aggregate formation in the cell.

38. The method of claim 1, wherein the method reduces the amount of preexisting tau aggregate formation in the cell.

39. A method of treating a tauopathy in a subject, comprising administering a LEM domain-containing protein 2 (LEMD2), a charged multivesicular body protein 7 (CHMP7), or an inner nuclear membrane protein Man 1 (LEMD3) or a nucleic acid encoding the LEMD2, the CHMP7, or the LEMD3 to the subject, wherein the LEMD2, the CHMP7, or the LEMD3 inhibits tau aggregation in a cell in the subject.

40. A method of preventing a tauopathy in a subject, comprising administering a LEM domain-containing protein 2 (LEMD2), a charged multivesicular body protein 7 (CHMP7), or an inner nuclear membrane protein Man 1 (LEMD3) or a nucleic acid encoding the LEMD2, the CHMP7, or the LEMD3 to the subject, wherein the LEMD2, the CHMP7, or the LEMD3 inhibits tau aggregation in a cell in the subject.

41-73. (canceled)

74. An expression construct comprising a nucleic acid encoding a LEM domain-containing protein 2 (LEMD2), a charged multivesicular body protein 7 (CHMP7), or an inner nuclear membrane protein Man 1 (LEMD3) operably linked to a heterologous promoter.

75-93. (canceled)