Preclinical Development of a Novel Gene Therapeutic for Inclusion Body Myositis

项目摘要。基因疗法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，是由炎症而非遗传引起的 突变。因此，它不能用基因替代或基因编辑方法来治疗，但仍然持久 需要基因疗法等解决方案来解决进行性肌肉退化问题。此类疗法 可能会彻底改变 IBM 患者的管理，特别是目前还没有获得批准的药物 治疗。 AAVogen 的长期目标是开发针对不同肌肉萎缩的基因疗法 疾病包括IBM。我们当前的目标是推进 AVGN7 (rAAV6:Smad7)，一种基因治疗药物 用于增强横纹肌质量和功能，用于 IBM 的临床试验。这得到了拟议的支持 向 FDA 提交 IND 所需的支持 IND 的临床前研究和监管会议。我们 假设 AVGN7 将显着增强 IBM 患者的肌肉质量和功能。确实， AVGN7 通过过度表达 SMAD7 来减弱 ActRIIb 配体（肌生长抑制素、激活素、GDF11）的作用， 它抑制肌肉细胞内的 ActRIIb 信号传导。这反过来又增加了肌肉蛋白质的合成， 抑制蛋白质降解并显着增强肌肉质量、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，包括那些患有高 炎症细胞因子和肌肉信号传导。最重要的是，AVGN7 避免了潜在的非常严重的情况 据报道，AVGN7 使用的肌生长抑制素配体陷阱和免疫疗法已停止使用，存在脱靶效应 具有高肌肉向性 (AAV6) 和 CK8 肌肉特异性启动子的载体。小鼠毒理学研究 最近完成了这些工作，并与 FDA 举行了监管会议，尽管 FDA 邀请我们 安排额外的会议来讨论临床和生产计划。因此，完成以下 里程碑将满足 IND 备案的关键要求，为首次人体试验做准备：(i) 保持最终结果 与 FDA 举行 IND 前会议，(ii) 在 IBM 的新型异种移植模型中生成概念验证数据，以及 (iii) 开发并验证抗药物免疫反应和生物分布测定。这些研究非常 意义重大，因为它们支持开发一种用于治疗 IBM 的新型基因疗法，IBM 是一种罕见且致残的疾病 专门影响老年人的疾病。正如 Milestone 2 研究一样，它们也具有高度创新性 利用迄今为止开发的最动态的 IBM 药物测试模型，因为 AVGN7 与所有其他模型不同 该领域的药物经过专门设计，具有卓越的功效、安全性和耐用性，因为它能够 长期减弱多种分解代谢信号，特别是肌肉中的信号。这些信号在大多数情况下都是保守的 如果不是所有的肌肉萎缩病症，这表明我们的方法可以广泛有效地治疗 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.