Development of a small-molecule that enhances tripartite synapses for Alzheimers disease

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Project Summary The best correlate of memory deficits in Alzheimer’s disease (AD) patients is not Aβ plaque burden or neurofibrillary tangles, but synapse loss, which is thought to occur early in the disease process before the onset of clinical symptoms. We have developed a novel compound called M3 that can effectively enhance structural and functional plasticity of synapses. This compound has been proved to provide significant benefits in two mouse models of AD (APPSw/Ind mice and rTg4510 mice), including improved cognitive functions, restored synaptic integrity, reduced neurodegeneration, reduced tau phosphorylation and neurofibrillary tangles, and reduced amyloid plaques. M3 has excellent potency, solubility, stability, specificity, and thus far no overt safety concerns. M3 meets all Late Stage Entry Criteria. In Year 1, we will focus on IND-enabling studies and IND preparation and filing. Our milestones are (i) completion of IND-enabling studies, (ii) production of a GMP batch for clinical studies, and (iii) active IND. In Year 2, we will focus on a single ascending dose (SAD) study. Our milestones are (i) IRB approval, (ii) completion of SAD study, and (iii) MTD and single dose PK established. In Year 3, we will focus on a multiple ascending dose (MAD) study. Our milestones are (i) completion of MAD study and (ii) MTD and repeat dose PK established.