Preclinical Development of a Novel Gene Therapeutic for Inclusion Body Myositis

项目总结。基因治疗为散发性包涵体肌炎(IBM)患者带来了希望。 这种慢性罕见疾病只影响老年人，是由炎症而不是遗传引起的。 突变。因此，它不能用基因替代或基因编辑的方法来治疗，但仍是持久的 需要像基因疗法这样的解决方案来解决进行性肌肉退化问题。这样的疗法 是否会彻底改变IBM患者的管理，特别是在目前没有批准的 治疗。AAVogen的长期目标是开发针对不同肌肉萎缩的基因疗法 包括IBM在内的疾病。我们目前的目标是发展AVGN7(rAAV6：Smad7)，一种基因治疗 用于增强横纹肌质量和功能，为IBM进行临床试验。这是由拟议的 IND-向FDA提交IND所需的临床前研究和监管会议。我们 假设AVGN7将显著增加IBM患者的肌肉质量和功能。的确， AVGN7通过过度表达SMAD7来减弱ActRIIb配体(myostatin，激活素，GDF11)的作用， 抑制肌肉细胞内的ActRIIb信号。这反过来又增加了肌肉蛋白质的合成， 抑制蛋白质降解，显著增强肌肉质量、力量和运动能力。它 还可以完全防止不同动物疾病模型中的肌肉萎缩，包括那些升高的 炎性细胞因子和肌肉信号。最重要的是，AVGN7避免了潜在的非常严重的 AVGN7使用时停用的肌肉生长抑素配体陷阱和免疫治疗的非靶点效应报告 具有高度肌肉趋向性的载体(AAV6)和CK8肌肉特异性启动子。小鼠毒理学研究 最近完成了，并与FDA举行了监管会议，尽管FDA邀请我们 安排额外的会议讨论临床和生产计划。因此，完成以下操作 里程碑将满足为第一人试验做准备的IND申请的关键要求：(I)举行最终 IND前与FDA的会议，(Ii)在IBM的一个新的异种移植模型中产生概念验证数据，以及(Iii) 开发和验证抗药物免疫反应和生物分布分析。这些研究是高度 因为它们支持开发一种治疗IBM的新基因疗法，IBM是一种罕见的致残疾病 仅影响老年人的疾病。作为里程碑2的研究，它们也具有很高的创新性 使用IBM开发的最动态的药物测试模型，因为AVGN7与所有其他模型不同 空间中的药物，是专门为卓越的疗效、安全性和耐用性而设计的，因为它能够 慢性衰减多种分解代谢信号，特别是肌肉。这些信号在大多数情况下是保守的 如果不是所有肌肉萎缩的情况，这表明我们的方法在治疗方面可能广泛有效 其他与年龄相关的肌肉萎缩疾病状态。

PROJECT SUMMARY. Gene therapy offers hope to patients with sporadic inclusion body myositis (IBM). This chronic rare disease exclusively affects older adults and results from inflammation rather than genetic mutations. Thus, it cannot be treated with gene replacement or gene editing approaches yet durable solutions like gene therapies are needed to address the progressive muscle degeneration. Such therapies could revolutionize the management of IBM patients especially as there are currently no approved treatments. AAVogen's long-term goal is to develop gene therapeutics for different muscle wasting diseases including IBM. Our current objective is to advance AVGN7 (rAAV6:Smad7), a gene therapeutic for enhancing striated muscle mass and function, to clinical trials for IBM. This is supported by the proposed IND-enabling preclinical studies and regulatory meetings that are required for IND filing with the FDA. We hypothesize that AVGN7 will significantly enhance muscle mass and function in IBM patients. Indeed, AVGN7 attenuates the actions of ActRIIb ligands (myostatin, activin, GDF11) by overexpressing SMAD7, which suppresses ActRIIb signaling inside the muscle cell. This in turn increases muscle protein synthesis, inhibits protein degradation and dramatically enhances muscle mass, strength and exercise capacity. It also completely prevents muscle wasting in different animal disease models including those with elevated inflammatory cytokines and muscle signaling. Most importantly, AVGN7 avoids the potentially very serious off-target effects reported for discontinued myostatin ligand traps and immunotherapeutics as AVGN7 uses a vector with high muscle tropism (AAV6) and the CK8 muscle-specific promoter. Mouse toxicology studies were recently completed and regulatory meetings with the FDA were held, although the FDA invited us to schedule additional meetings to discuss clinical and manufacturing plans. Thus, completing the following Milestones will satisfy critical requirements for an IND filing in preparation for first-in-man trials: (i) hold final pre-IND meeting with FDA, (ii) generate proof-of-concept data in a novel xenograft model of IBM and (iii) develop and validate anti-drug immune response and biodistribution assays. These studies are highly significant as they support development of a novel gene therapeutic for treating IBM, a rare and disabling disease that exclusively affects older adults. They are also highly innovative as the Milestone 2 studies utilize the most dynamic model for IBM drug testing ever developed and because AVGN7, unlike all other drugs in the space, was specifically designed for superior efficacy, safety and durability due to its ability to chronically attenuate multiple catabolic signals specifically in muscle. These signals are conserved in most if not all muscle wasting conditions, suggesting that our approach could be broadly effective in treating other age-related muscle wasting disease states.