Phase II year
2017
(last award dollars: 2021)
Phase II Amount
$2,002,000
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.
Public Health Relevance Statement: RELEVANCE TO PUBLIC HEALTH. The striated muscle wasting that occurs with cancer cachexia compromises quality of life and is both directly and indirectly responsible for cancer mortalities. The proposed studies will develop a novel gene therapy for preventing this wasting, whether it results from tumor burden or chemotherapy. These studies will also advance the gene therapy towards clinical trials by completing the required toxicology studies.
Project Terms: Activins; adeno-associated viral vector; Affect; Antibodies; Attenuated; base; Benchmarking; Blood Vessels; Cachexia; cancer cachexia; Cancer Model; Cancer Patient; cancer therapy; Catabolism; chemotherapy; Chemotherapy-Oncologic Procedure; Cisplatin; Clinical assessments; Clinical Medicine; Clinical Treatment; Clinical Trials; Colon Adenocarcinoma; cytokine; Data; Development; Energy Intake; exercise capacity; experience; experimental study; GDF11 gene; GDF8 gene; gene therapy; Goals; Hemophilia A; Hormones; IGF1 gene; Impairment; Implant; improved; Inherited; innovation; Intervention; Ligands; Longevity; MADH7 gene; Malignant Neoplasms; meetings; Mitogens; mortality; mouse model; Mus; muscle form; Muscle function; Muscle Proteins; muscle regeneration; Muscular Atrophy; Muscular Dystrophies; muscular structure; nonhuman primate; novel; nutrition; Nutritional Support; Outcome; overexpression; Patients; Phase; phase 2 study; Preparation; prevent; Production; Protein Biosynthesis; Proteins; Public Health; Quality Control; Quality of life; Radiation therapy; Recombinants; Research; Retinal Dystrophy; Signal Pathway; Signal Transduction; skeletal muscle wasting; Striated Muscles; System; Technology; Testing; Therapeutic; therapeutic gene; tool; Toxicology; translational study; Treatment outcome; tumor; Tumor Burden; tumor growth; Tumor-Derived; wasting; Wild Type Mouse
