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

Vivreon Biosciences，LLC 4940卡罗尔峡谷路，Ste. 110 San Diego，CA milton@vivreonbiosciences.com NIA PAS-19-316 项目摘要 将阿尔茨海默病（AD）的发病时间推迟5年将使美国的医疗费用减少三分之一。 在AD中，激活的脑小胶质细胞的神经毒性炎症导致突触损失和突触内毒素的积累。 不适当聚集的蛋白质，如淀粉样蛋白。生产性小胶质细胞反应通常是短暂的， 有效清除感染因子或细胞碎片，并涉及吞噬和其他修复过程。 一种恢复修复性与破坏性神经毒性小胶质细胞反应平衡的疗法， 假设可以减少突触损伤，减缓疾病进展。Ca 2+释放激活的Ca 2+（CRAC） 通过暗示CRAC通道的遗传证据，支持CRAC通道作为AD治疗的药物靶点 信号通路CRAC通道被小胶质细胞上的多种受体激活，下游信号传导 驱动多种生物化学和基因表达事件典型的破坏性神经毒性炎症 由NFAT启动子驱动。 Vivreon Biosciences寻求通过选择和推进领先的CRAC来控制AD进展 调节化合物VV 8325进入药物开发管道。VV 8325是口服可利用的， 渗透剂，对CRAC通道有效，在初始安全测试中具有吸引力。Vivreon CRAC通道 调节剂选择性抑制神经毒性小胶质细胞炎症，同时促进有益的吞噬和 在不加重病毒挑战的情况下存活。此外，我们假设Aβ和细胞死亡 相关的生物分子如ADP通过小胶质细胞CRAC通道驱动持续的Ca 2+信号传导，导致AD 在病理学上，TREM 2-R47 H等位基因的人的过程加剧。在这个第二阶段的项目中，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VV 8325，包括，最大 耐受剂量确定、7天剂量范围确定和优化生产参数， 生产100克批次。将在两种AD模型中测试化合物功效。首先，我们将测量 验证的5XFAD模型中的VV 8325功效以证明治疗剂量-反应，确定ED 50 并验证我们的候选生物标志物。最佳有效临床试验设计指南，VV 8325 人诱导多能干细胞小胶质细胞（iMGL）对神经毒性炎症激活的功效 将在体内测试携带TREM 2-R47 H变体的细胞。TREM 2-R47 H变体在人类中增强CRAC 信号传导是AD风险的遗传标记，并且该群体可以提供靶向试验队列。该项目将 最终在携带TREM 2-R47 H人小胶质细胞的独特模型中进行VV 8325的体内功效测试。 这使得我们能够测试携带变异体的患者是否可以通过VV 8325更有效地治疗， 指向TERM 2-R47 H基因型靶向的初始疗效临床试验设计。VV 8325在此获得成功 将吸引外部资金支持，以促进这一有前途的疗法。

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.