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

项目摘要 阿尔茨海默病（AD）患者记忆缺陷的最佳相关因素不是Aβ斑块负荷或 神经元缠结，但突触损失，这被认为是发生在疾病过程的早期， 临床症状的出现。我们开发了一种名为M3的新型化合物， 增强突触的结构和功能可塑性。该化合物已被证明提供 在两种AD小鼠模型（APPSw/Ind小鼠和rTg 4510小鼠）中的显著益处，包括改善 认知功能，恢复突触完整性，减少神经变性，减少tau磷酸化 和神经纤维缠结，减少淀粉样斑块。M3具有优异的效力、溶解性、稳定性， 特异性，到目前为止没有明显的安全性问题。M3符合所有后期阶段进入标准。在第一年，我们 将专注于IND启动研究和IND准备和备案。我们的里程碑是（i）完成 IND使能研究，（ii）生产用于临床研究的GMP批次，以及（iii）活性IND。在第2年，我们 将重点关注单次递增剂量（SAD）研究。我们的里程碑是（i）IRB批准，（ii）完成 SAD研究，和（iii）确定MTD和单次给药PK。在第三年，我们将专注于多个 递增剂量（MAD）研究。我们的里程碑是（i）完成MAD研究和（ii）MTD和重复 确定的剂量PK。

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.