Preclinical Characterization of CRAC Channel Inhibitors for the Treatment of Alzheimer's Disease

Vivreon生物科学有限责任公司 圣卡罗尔峡谷路4940号110 加州圣地亚哥，邮编92121 邮箱：milton@vivreonbiosciences.com NIA PAS-19-316 项目摘要 将阿尔茨海默病(AD)的发病推迟5年将使美国的医疗成本减少三分之一。 在AD中，激活的脑小胶质细胞的神经毒性炎症导致突触丢失和 不正确聚集的蛋白质，如淀粉样蛋白。生产性的小胶质细胞反应通常是瞬时的， 有效清除感染物或细胞碎片，并涉及吞噬和其他修复过程。 一种恢复修复性和破坏性神经毒性小胶质反应的平衡的疗法是 假想是为了减少突触损伤，减缓疾病进展。钙释放激活钙(CRAC) 通道，作为AD治疗的药物靶点，被涉及CRAC通道的遗传证据所支持 信号通路。CRAC通道被小胶质细胞上的多个受体激活，下游信号 导致多种生化和基因表达事件，典型的破坏性神经毒性炎症 由NFAT的推动者驱动。 Vivreon Biosciences寻求通过选择和提拔一位首席CRAC来控制AD进展 将化合物VV8325调制到药物开发流水线中。VV8325可口服和脑 渗透性强，对CRAC通道具有强大的抵抗力，在初步安全测试中具有吸引力。伟锐CRAC频道 调节剂选择性地抑制神经毒性小胶质细胞炎症，同时促进有益的吞噬细胞和 在不加剧病毒挑战的情况下发挥生存功能。此外，我们假设Aβ和细胞死亡 ADP等相关生物分子通过小胶质细胞CRAC通道维持钙信号，导致AD 病理学，TREM2-R47H等位基因携带者的一个过程加剧。在此第二阶段项目中，我们建议 通过完成药物代谢和药代动力学研究进一步鉴定VV8325，包括 耐受剂量测定、7天剂量范围确定和优化制造参数 生产100克的批次。将在两种AD模型上测试复合疗效。首先，我们将测量 VV8325在验证的5XFAD模型中的有效性，以展示治疗剂量-反应，确定ED50 并确认我们的候选生物标记物。指导最有效的临床试验设计--VV8325 抗人诱导多能干细胞小胶质细胞神经毒性炎症激活的作用 TREM2-R47H变种的轴承将在体内进行测试。人类TREM2-R47H变异可增强CRAC 信号，是AD风险的遗传标记，人群可能提供有针对性的试验队列。该项目将 在携带TREM2-R47H人小胶质细胞的独特模型上完成VV8325的体内疗效测试 这使我们能够测试VV8325是否可以更有效地治疗变异携带者 指向针对TERM2-R47H基因的初始疗效临床试验设计。VV8325在这里取得成功 将为这一有希望的疗法的发展吸引外部资金支持。

Vivreon Biosciences, LLC 4940 Carroll Canyon Rd., Ste. 110 San Diego, CA 92121 milton@vivreonbiosciences.com NIA PAS-19-316 Project Summary Delaying onset of Alzheimer’s Disease (AD) by 5 years would reduce US healthcare costs by one third. In AD, the neurotoxic inflammation of activated brain microglia results in synapse loss and accumulation of improperly aggregated proteins such as amyloid . Productive microglial responses are normally transient, effectively clearing infectious agents or cellular debris, and involve phagocytic and other reparative processes. A therapy that restores the balance of reparative versus damaging neurotoxic microglial responses is hypothesized to reduce synaptic damage, slowing disease progression. The Ca2+ release-activated Ca2+ (CRAC) channel, is supported as a drug target for AD therapy by genetic evidence implicating the CRAC channel signaling pathway. The CRAC channel is activated by multiple receptors on microglia, and downstream signaling drives a multiplicity of biochemical and gene expression events typical of damaging neurotoxic inflammation driven by the NFAT promoter. Vivreon Biosciences seeks to control AD progression by selecting and advancing a lead CRAC modulating compound, VV8325, into the drug development pipeline. VV8325 is orally available and brain penetrant, potent against the CRAC channel and attractive in initial safety tests. Vivreon CRAC channel modulators selectively inhibit neurotoxic microglial inflammation while promoting beneficial phagocytic and survival functions without aggravating a viral challenge. Further, we hypothesize that Aβ and cell death associated biomolecules like ADP drive sustained Ca2+ signaling by microglial CRAC channels, resulting in AD pathology, a process intensified in persons with the TREM2-R47H allele. In this Phase 2 project we propose to further qualify VV8325 via completion of drug metabolism and pharmacokinetic studies including, maximal tolerated dose determination, 7-day dose range finding, and optimizing manufacturing parameters towards production of a 100 gram batch. Compound efficacy will be tested in two models of AD. First, we will measure VV8325 efficacy in a validated 5XFAD model to demonstrate a therapeutic dose-response, determine an ED50 and validate our candidate biomarker. Towards guidance of an optimally efficient clinical trial design, VV8325 efficacy against neurotoxic inflammatory activation of human induced pluripotent stem cell microglia (iMGL) bearing the TREM2-R47H variant will be tested in vivo. The TREM2-R47H variant in humans enhances CRAC signaling, is a genetic marker of AD risk and the population may provide a targeted trial cohort. The project will culminate in an in vivo efficacy test of VV8325 in a unique model carrying TREM2-R47H human microglia allowing us to test whether the variant-bearing patients may be more effectively treated by VV8325 and thus point towards a TERM2-R47H genotype-targeted initial efficacy clinical trial design. Success for VV8325 here will attract external funding support for advancement of this promising therapy.