AVGN7, a Novel Gene Therapeutic for Treating Cancer Cachexia

AVGN7，一种治疗癌症恶病质的新型基因疗法

• 批准号: 9408490
• 负责人: Buel Rodgers
• 金额: $ 120.7万
• 依托单位: AAVOGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-25 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9408490
• 关键词: Activins; Affect; Antibodies; Attenuated; Benchmarking; Blood Vessels; Cachexia; Cancer Model; Cancer Patient; Catabolism; Chemotherapy-Oncologic Procedure; Cisplatin; Clinical Medicine; Clinical Treatment; Clinical Trials; Clinical assessments; Colon Adenocarcinoma; Data; Development; Energy Intake; GDF11 gene; GDF8 gene; Goals; Hemophilia A; Hormones; IGF1 gene; Impairment; Implant; Inherited; Intervention; Ligands; Longevity; MADH7 gene; Malignant Neoplasms; Mitogens; Mus; Muscle Proteins; Muscle function; Muscular Atrophy; Muscular Dystrophies; Nutritional Support; Outcome; Patients; Phase; Preparation; Production; Protein Biosynthesis; Proteins; Public Health; Quality Control; Quality of life; Radiation therapy; Recombinants; Research; Retinal Dystrophy; Signal Pathway; Signal Transduction; Striated Muscles; System; Technology; Testing; Therapeutic; Toxicology; Treatment outcome; Tumor Burden; Tumor-Derived; Wild Type Mouse; adeno-associated viral vector; base; cancer cachexia; cancer therapy; chemotherapy; cytokine; exercise capacity; experience; experimental study; gene therapy; improved; innovation; meetings; mortality; mouse model; muscle form; muscle regeneration; muscular structure; nonhuman primate; novel; nutrition; overexpression; phase 2 study; prevent; skeletal muscle wasting; therapeutic gene; tool; translational study; tumor; tumor growth; wasting

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.

项目摘要。癌症恶病质妥协发生的骨骼肌浪费 生活质量，既直接和间接负责癌症死亡率。肿瘤衍生和 肿瘤反应性因素以及许多治疗剂本身都为缓存状态做出了贡献， 尽管营养支持对恢复条纹肌肉质量或功能的积极影响几乎没有。 因此，预防癌症患者肌肉浪费的新工具可以改变他们的治疗， 显着改善了他们的生活质量。我们的研究目标是测试一种新型的基因治疗方法 在肿瘤和化学疗法诱导的恶病质的小鼠模型中增强肌肉再生 此外，以完成IND归档所需的GLP/毒理学研究。我们假设那削弱了 负责肌肉萎缩和肌肉再生受损的细胞内信号传导途径将 反过来恢复肌肉质量和功能，并显着延迟死亡率。实际上，第一阶段等效 数据表明，用RAAV6：SMAD7（又称AVGN7）衰减Actriib和Smad2/3信号传导 显着增强野生型小鼠的肌肉质量和功能，可以完全防止肌肉 癌症恶病质小鼠模型中的萎缩。最重要的是，这种治疗方法没有 产生严重的脱靶效应，损害了竞争技术的发展 已被证明会损害血管完整性或具有这种潜力。我们的 具体目的是（i）检验Raav6：Smad7可以预防癌症和化学疗法的假设。 诱导的肌肉浪费，（ii）检验了Raav6：Smad7降低癌症死亡率和（iii）的假设 通过RAAV6：SMAD7的完整鼠和非人类灵长类动物毒理学研究。提议 方法确实具有创新性，因为它利用一种新型的基因治疗和最先进的工具来 全面评估不同尺度的肌肉功能。这些研究也非常重要，因为 他们将对肿瘤和化学疗法诱导的肌肉的方法提供更好的理解 浪费受Actriib和Smad2/3信号的独立影响。最重要的是，这些 翻译研究具有影响临床医学并推进临床试验的真正潜力 raav6：smad7。