AVGN7, a Novel Gene Therapeutic for Treating Cancer Cachexia

项目摘要。癌症恶病质引起的骨骼肌萎缩 生活质量，并直接和间接导致癌症死亡。肿瘤衍生和 肿瘤应答因子以及许多治疗剂本身促成恶病质状态， 尽管营养支持对恢复横纹肌质量或功能几乎没有任何积极作用。 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， 大大提高了他们的生活质量。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的恶病质小鼠模型中的肌肉再生， 此外，完成IND备案所需的GLP/毒理学研究。我们假设衰减 导致肌肉萎缩和受损肌肉再生的细胞内信号传导途径将 从而恢复肌肉质量和功能并显著延迟死亡。事实上，I期等效 数据表明用rAAV 6：Smad 7（a.k.a. AVGN 7） 显著增强野生型小鼠的肌肉质量和功能， 在不同的癌症恶病质小鼠模型中的萎缩。最重要的是，这种治疗方法不会 产生严重的脱靶效应，损害竞争技术的发展 已经被证明会损害血管完整性或具有这种潜力。我们 具体目标是（i）测试rAAV 6：Smad 7可以预防癌症和化疗的假设 诱导的肌肉消耗，（ii）测试rAAV 6：Smad 7降低癌症死亡率的假设和（iii） 用rAAV 6：Smad 7完成鼠和非人灵长类动物毒理学研究。拟议 这种方法是真正的创新，因为它利用了一种新的基因治疗和最先进的工具， 在不同的尺度上全面评估肌肉功能。这些研究也非常重要， 他们将提供一个更好的机制理解肿瘤和化疗诱导的肌肉 消耗独立地受到ActRIIB和Smad 2/3信号传导的影响。最重要的是，这些 转化研究具有影响临床医学和推进临床试验的真实的潜力 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.