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: 10011562
• 负责人: Buel Rodgers
• 金额: $ 13.48万
• 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 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10011562
• 关键词: Activins; Affect; Antibodies; Attenuated; Benchmarking; Blood Vessels; C26 tumor; 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; 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。癌症恶病质损害导致骨骼肌萎缩 生活质量，直接和间接地导致癌症死亡率。肿瘤源性和 肿瘤反应因子以及许多治疗方法本身都会导致恶病质状态， 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 显着提高他们的生活质量。我们的研究目标是测试一种新型基因疗法 增强肿瘤和化疗引起的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 导致肌肉萎缩和肌肉再生受损的细胞内信号通路将 进而恢复肌肉质量和功能并显着延迟死亡率。事实上，I 期等效 数据表明，rAAV6:Smad7（又名 AVGN7）可减弱 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，并能完全预防肌肉萎缩 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 产生严重的脱靶效应，影响竞争技术的发展 已被证明会损害血管完整性或具有这种潜力。我们的 具体目标是 (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，以及 (iii) 使用 rAAV6:Smad7 完成小鼠和非人类灵长类动物毒理学研究。拟议的 该方法确实具有创新性，因为它利用新颖的基因治疗和最先进的工具来 综合评估不同尺度的肌肉功能。这些研究也非常重要，因为 他们将提供对肿瘤和化疗如何诱导肌肉损伤的更好的机制理解。 ActRIIB 和 Smad2/3 信号传导独立影响消瘦。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正潜力 rAAV6:Smad7。

项目成果

Myostatin/Activin Receptor Ligands in Muscle and the Development Status of Attenuating Drugs.

• DOI: 10.1210/endrev/bnab030
• 发表时间: 2022-03-09
• 期刊: Endocrine reviews
• 影响因子: 20.3
• 作者: Rodgers BD;Ward CW
• 通讯作者: Ward CW

Development and validation of a model gene therapy biodistribution assay for AVGN7 using digital droplet polymerase chain reaction.

• DOI: 10.1016/j.omtm.2023.05.007
• 发表时间: 2023-06-08
• 期刊: MOLECULAR THERAPY METHODS & CLINICAL DEVELOPMENT
• 作者: Rodgers, Buel D.;Herring, Sarah K.;Carias, Dereck R.;Chen, Joyce;Rocha, Agostinho G.
• 通讯作者: Rocha, Agostinho G.