AVGN7, a Novel Gene Therapeutic for Treating Cancer Cachexia

项目总结。癌症恶病质引起的骨骼肌萎缩 并对癌症死亡率负有直接和间接的责任。肿瘤来源和 肿瘤反应因子以及许多治疗药物本身都会导致恶病质状态， 虽然营养支持在恢复横纹肌质量或功能方面几乎没有积极作用。 因此，预防癌症患者肌肉萎缩的新工具可以改变他们的治疗方法和 显著提高他们的生活质量。我们的研究目标是测试一种新的基因治疗方法 增强肿瘤和化疗诱导恶病质小鼠模型的肌肉再生 此外，完成IND备案所需的GLP/毒理学研究。我们假设衰减剂 导致肌肉萎缩和肌肉再生受损的细胞内信号通路将 反过来，恢复肌肉质量和功能，显着延缓死亡。事实上，第一阶段--等值 数据表明，用rAAV6：Smad7(又名：AVGN7) 显著增强野生型小鼠的肌肉质量和功能，并能完全防止肌肉 不同癌症恶病质小鼠模型中的萎缩。最重要的是，这种疗法不会 产生严重的偏离目标的影响，损害了竞争技术的发展 它们要么被证明危害血管完整性，要么具有这种潜力。我们的 具体目的是(I)检验rAAV6：Smad7可以预防癌症和化疗的假设 诱导肌肉萎缩，(Ii)检验rAAV6：Smad7降低癌症死亡率的假设和(Iii) 使用rAAV6：Smad7完成小鼠和非人类灵长类动物的毒理学研究。建议数 方法是真正创新的，因为它利用了一种新的基因治疗和最先进的工具来 综合评估不同级别的肌肉功能。这些研究也非常有意义，因为 他们将提供一个更好的机制来理解肿瘤和化疗如何诱导肌肉 消耗独立地受到ActRIIB和Smad2/3信号的影响。最重要的是，这些 翻译研究具有影响临床医学和推进临床试验的非常真实的潜力。 RAAV6：Smad7。

PROJECT SUMMARY. The skeletal muscle wasting that occurs with cancer cachexia compromises quality of life and is both directly and indirectly responsible for cancer mortalities. Tumor-derived and tumor-responsive factors as well as many therapeutics themselves contribute to the cachectic state, although nutritional support has little if any positive effect on restoring striated muscle mass or function. Thus, novel tools for preventing muscle wasting in cancer patients could transform their treatment and significantly improve their quality of life. Our research objective is to test a novel gene therapeutic for enhancing muscle regeneration in a mouse model of tumor- and chemotherapy-induced cachexia and in addition, to complete the GLP/toxicology studies required for IND filing. We hypothesize that attenuating the intracellular signaling pathways responsible for muscle atrophy and impaired muscle regeneration will in turn restore muscle mass and function and significantly delay mortality. In fact, Phase I-equivalent data indicate that attenuating ActRIIB and Smad2/3 signaling with rAAV6:Smad7 (a.k.a. AVGN7) significantly enhances muscle mass and function in wild-type mice and can completely prevent muscle atrophy in different mouse models of cancer cachexia. Most importantly, this therapeutic does not produce the serious off-target effects that have compromised development of competing technologies that have either been shown to compromise blood vessel integrity or to possess this potential. Our specific aims are to (i) test the hypothesis that rAAV6:Smad7 can prevent cancer- and chemotherapy- induced muscle wasting, (ii) test the hypothesis that rAAV6:Smad7 reduces cancer mortality and (iii) complete murine and non-human primate toxicology studies with rAAV6:Smad7. The proposed approach is truly innovative as it utilizes a novel gene therapeutic and state-of-the art tools to comprehensively assess muscle function at different scales. These studies are also highly significant as they will provide a better mechanistic understanding of how tumor- and chemotherapy-induced muscle wasting are independently affected by ActRIIB and Smad2/3 signaling. Most importantly, these translational studies have the very real potential to impact clinical medicine and to advance clinical trials of rAAV6:Smad7.