Research Project
10322074
7. Project Summary AD In response to PAS-19-319, Creative Bio-Peptides, Inc. proposes a novel therapeutic approach to protect and restore synapses in Alzheimer?s Disease (AD) by blocking multiple chemokine receptors that promote synapse loss and inhibit their regeneration. Functional impairment in AD results from loss of neuronal spines and dendrites, preceding and independent of neuronal death. Cofilin-actin rods (rods) are a 1:1 complex of actin and cofilin whose formation is linked to a cellular prion protein (PrPC) and NADPH oxidase (NOX)-dependent signaling pathway and represents an early AD pathology. Rods form in neurites under conditions of energetic and oxidative stress, such as occur in neuroinflammation, and lead to neurite distal atrophy. Synapse function declines in neurites in which rods have formed compared neurites without rods from the same neuron and rods are significantly increased in animal models of AD and in human AD brain. Conversely, cognitive deficits in mouse models of AD are alleviated by decreasing cofilin rods in neurons. Cofilin plays important roles in dendritic spine dynamics and receptor trafficking and the sequestering of cofilin into rods is detrimental to synaptic function. Our preliminary data shows that new oral, stable and rapidly brain penetrant peptide analogs of the clinical use multi-chemokine receptor antagonist (mCRA) DAPTA (Dala1-peptide T-amide) inhibit the formation of A?d/t (1 nM)-induced cofilin-actin rods and are neuroprotective. DAPTA reduced microglial activation in the dentate gyrus, prevented cortical neuronal loss in NBM-lesioned aged animals and promoted robust sprouting of axons and synapse regeneration in animals. In multiple phase 2 trials conducted by the NIH on subjects with HIV-associated neurocognitive disorders (HAND), DAPTA normalized functional brain scans and reversed cognitive deficits in phase 2 trials by chemokine receptor blocking mechanisms related to preventing cofilin rod formation and protecting synapses. The synapse and neurite extending effects of chemokine blockade were recently also shown for maraviroc in brain injuries confirming chemokine receptors as translational targets for drug development. DAPTA was safe in over 600 persons, some for as long as ten years however was not stable as a nasal spray formulation. It took us many years to create new stable oral analogs of DAPTA with better brain entry and long half-life and now propose to optimize a lead oral peptide for synapse protecting and restoring benefits in AD by determining the EC50 values for four oral peptides to inhibit formation of A?d/t-induced cofilin rods compared to approved CRA?s maraviroc and AMD3100 in primary mouse hippocampal neuronal cultures. We will further optimize the neuroprotective effects of peptides in A?d/t-treated neurons through quantifiable morphological and architectural assessments of synapse morphology. Once we have identified the optimized peptide, we will determine the safety and toxicokinetic profile and confirm brain entry as a prelude to future IND- enabling studies.
