Preclinical Development of a Novel Gene Therapeutic for Inclusion Body Myositis

包涵体肌炎新基因疗法的临床前开发

• 批准号: 10601641
• 负责人: Buel Rodgers
• 金额: $ 90.41万
• 依托单位: AAVOGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10601641
• 关键词: Activins; Address; Affect; Animal Disease Models; Animals; Antibodies; Attenuated; Biodistribution; Biological Assay; Biopsy; Chemistry; Chronic; Clinical; Clinical Trials; Cytokeratin-8 Staining Method; DNA Sequence Alteration; Data; Degenerative Disorder; Development; Disease; Effectiveness; Elderly; FBXO32 gene; Feedback; Foundations; Functional disorder; GDF11 gene; GDF8 gene; Genes; Goals; Heart Diseases; Hip Fractures; Histology; Immune response; Immunotherapeutic agent; Inclusion Bodies; Inclusion Body Myositis; Inflammation; Inflammatory; Kidney Failure; Ligands; MADH2 gene; MADH7 gene; Medical; Modality; Modeling; Mus; Muscle; Muscle Cells; Muscle Fibers; Muscle Proteins; Muscle function; Muscular Atrophy; Myositis; Myotonic Dystrophy; Names; Neuromuscular Diseases; Patients; Pharmaceutical Preparations; Phase I/II Clinical Trial; Preparation; Program Development; Progressive Disease; Protein Biosynthesis; Public Health; Rare Diseases; Recombinants; Regulatory Affairs; Renal carcinoma; Reporting; Safety; Schedule; Signal Transduction; Sporadic Inclusion Body Myopathy; Striated Muscles; Technology; Testing; Therapeutic; Toxicology; Translating; Transplantation; Tropism; Wasting Syndrome; Xenograft Model; adeno-associated viral vector; age related; age-related muscle loss; base; cancer cachexia; cell mediated immune response; congenital heart disorder; cytokine; design; disabling disease; drug testing; exercise capacity; first-in-human; gene replacement; gene therapy; innovation; meetings; muscle degeneration; muscle form; novel; overexpression; pre-clinical; preclinical development; preclinical study; prevent; promoter; protein degradation; sarcopenia; success; therapeutic gene; ubiquitin-protein ligase; vector

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.

项目摘要。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，由炎症而不是遗传引起。 突变。因此，它不能用基因替换或基因编辑方法治疗，但持久 需要像基因疗法这样的解决方案来解决进行性肌肉退化。此类疗法 可能会彻底改变IBM患者的管理，特别是因为目前还没有批准的 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。我们目前的目标是推进AVGN 7（rAAV6：Smad7），一种基因治疗剂， 用于增强横纹肌质量和功能，用于IBM的临床试验。这一点得到了建议的支持。 向FDA提交IND申请所需的IND支持临床前研究和监管会议。我们 假设AVGN 7将显著增强IBM患者的肌肉质量和功能。的确， AVGN 7通过过表达SMAD 7减弱ActRIIb配体（肌生长抑制素、激活素、GDF 11）的作用， 从而抑制肌细胞内的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，包括那些具有升高的 炎性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 AVGN 7使用时，报告了停止使用肌生长抑制素配体捕获剂和免疫治疗剂的脱靶效应 具有高肌肉向性的载体（AAV6）和CK8肌肉特异性启动子。小鼠毒理学研究 最近完成了与FDA的监管会议，尽管FDA邀请我们 安排额外的会议来讨论临床和制造计划。因此，完成以下工作 Mildrone将满足IND申请的关键要求，为首次人体试验做准备：（i）保持最终 与FDA的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） 开发和验证抗药免疫反应和生物分布测定。这些研究高度 重要的是，他们支持开发一种新的基因治疗方法来治疗IBM，一种罕见的致残性疾病。 只影响老年人的疾病。它们也是高度创新的，因为里程碑2研究 AVGN 7使用IBM药物测试有史以来开发的最动态的模型，因为AVGN 7与所有其他模型不同， 药物的空间，是专门设计的上级疗效，安全性和耐用性，由于其能力， 长期减弱肌肉中的多种分解代谢信号。这些信号在大多数 如果不是所有的肌肉萎缩状况，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。