Gene therapy offers hope to patients with sporadic inclusion body myositis (IBM). This chronic rare disease exclusively affects older adults and results from inflammation rather than genetic mutations. Thus, it cannot be treated with gene replacement or gene editing approaches yet durable solutions like gene therapies are needed to address the progressive muscle degeneration. Such therapies could revolutionize the management of IBM patients especially as there are currently no approved treatments. AAVogen's long-term goal is to develop gene therapeutics for different muscle wasting diseases including IBM. Our current objective is to advance AVGN7 (rAAV6:Smad7), a gene therapeutic for enhancing striated muscle mass and function, to clinical trials for IBM. This is supported by the proposed IND-enabling preclinical studies and regulatory meetings that are required for IND filing with the FDA. We hypothesize that AVGN7 will significantly enhance muscle mass and function in IBM patients. Indeed, AVGN7 attenuates the actions of ActRIIb ligands (myostatin, activin, GDF11) by overexpressing SMAD7, which suppresses ActRIIb signaling inside the muscle cell. This in turn increases muscle protein synthesis, inhibits protein degradation and dramatically enhances muscle mass, strength and exercise capacity. It also completely prevents muscle wasting in different animal disease models including those with elevated inflammatory cytokines and muscle signaling. Most importantly, AVGN7 avoids the potentially very serious off-target effects reported for discontinued myostatin ligand traps and immunotherapeutics as AVGN7 uses a vector with high muscle tropism (AAV6) and the CK8 muscle-specific promoter. Mouse toxicology studies were recently completed and regulatory meetings with the FDA were held, although the FDA invited us to schedule additional meetings to discuss clinical and manufacturing plans. Thus, completing the following Milestones will satisfy critical requirements for an IND filing in preparation for first-in-man trials: (i) hold final pre-IND meeting with FDA, (ii) generate proof-of-concept data in a novel xenograft model of IBM and (iii) develop and validate anti-drug immune response and biodistribution assays. These studies are highly significant as they support development of a novel gene therapeutic for treating IBM, a rare and disabling disease that exclusively affects older adults. They are also highly innovative as the Milestone 2 studies utilize the most dynamic model for IBM drug testing ever developed and because AVGN7, unlike all other drugs in the space, was specifically designed for superior efficacy, safety and durability due to its ability to chronically attenuate multiple catabolic signals specifically in muscle. These signals are conserved in most if not all muscle wasting conditions, suggesting that our approach could be broadly effective in treating other age-related muscle wasting disease states.
Public Health Relevance Statement: RELEVANCE TO PUBLIC HEALTH. Sporadic inclusion body myositis (IBM) is a chronic rare disease that exclusively affects older adults, inducing muscle wasting and dysfunction. The proposed studies will develop a novel gene therapeutic that not only prevents such losses, but also restores muscle mass and function. Project success will address a substantial unmet medical and public health need as there are currently no approved treatments for IBM.
Project Terms: Affect; Elderly; advanced age; elders; geriatric; late life; later life; older adult; older person; senior citizen; Animals; Antibodies; Biological Assay; Assay; Bioassay; Biologic Assays; Biopsy; Inclusion Bodies; Cellular Inclusions; Chemistry; Clinical Trials; Disease; Disorder; Animal Disease Models; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Feedback; Foundations; gene therapy; DNA Therapy; Gene Transfer Clinical; Genetic Intervention; gene repair therapy; gene-based therapy; genetic therapy; genomic therapy; Genes; Goals; Heart Diseases; Cardiac Diseases; Cardiac Disorders; heart disorder; Hip Fractures; Histology; Inflammation; Ligands; Mus; Mice; Mice Mammals; Murine; Muscle Proteins; Muscle; Muscle Tissue; muscular; Muscular Atrophy; Muscle Atrophy; muscle breakdown; muscle degradation; muscle deterioration; muscle loss; muscle wasting; Inflammatory Muscle Diseases; Inflammatory Myopathy; Myositis; Dystrophia Myotonica; Myotonia Atrophica; Myotonia Dystrophica; Steinert Disease; dystrophic myotonia; Myotonic Dystrophy; Names; myoneural disorder; neuromuscular degenerative disorder; neuromuscular disorder; Neuromuscular Diseases; Patients; Program Development; Public Health; Kidney Insufficiency; Renal Failure; Renal Insufficiency; Kidney Failure; Safety; Cell Communication and Signaling; Cell Signaling; Intracellular Communication and Signaling; Signal Transduction Systems; Signaling; biological signal transduction; Signal Transduction; Technology; Testing; Toxicology; Translating; Transplantation; transplant; Wasting Syndrome; Wasting Disease; wasting condition; wasting disorder; Activins; FSH-Releasing Protein; ubiquitin-protein ligase; E3 Ligase; E3 Ubiquitin Ligase; Ubiquitin Protein Ligase; Ubiquitin-Protein Ligase Complexes; Ubiquitin-Protein Ligase E3; cytokine; promoter; promotor; Schedule; congenital heart disorder; congenital cardiac abnormality; congenital cardiac disease; congenital cardiac disorder; congenital cardiac malformation; congenital heart abnormality; congenital heart anomaly; congenital heart disease; congenital heart malformation; base; Chronic; Clinical; Medical; Muscle function; muscle degeneration; inclusion-body myosytis; Inclusion Body Myositis; muscle bulk; muscle mass; muscle form; Myotubes; Rhabdomyocyte; Skeletal Fiber; Skeletal Muscle Cell; Skeletal Muscle Fiber; Skeletal Myocytes; Muscle Fibers; Tropism; Dysfunction; Physiopathology; pathophysiology; Functional disorder; Immunological response; host response; immune system response; immunoresponse; Immune response; Therapeutic; Attenuated; Inflammatory; meetings; disabling disease; Myocytes; Muscle Cells; Ribosomal Peptide Biosynthesis; Ribosomal Protein Biosynthesis; Ribosomal Protein Synthesis; protein synthesis; Protein Biosynthesis; Metabolic Protein Degradation; Protein Turnover; Regulatory Protein Degradation; protein degradation; success; Orphan Disease; Rare Disorder; orphan disorder; Rare Diseases; novel; Modality; Reporting; Sporadic Inclusion Body Myositis; Sporadic Inclusion Body Myopathy; Modeling; sarcopenic; sarcopenia; gene replacement; immune drugs; immune-based therapeutics; immunologic preparation; immunologic therapeutics; immunotherapeutics; immunotherapy agent; Immunotherapeutic agent; Effectiveness; degenerative condition; degenerative disease; Degenerative Disorder; preventing; prevent; cell mediated immune response; Striated Muscles; GDF-8; GDF8; Growth Differentiation Factor 8 Gene; Growth/Differentiation Factor 8; MSTN; growth-differentiation factor 8; myostatin; GDF8 gene; JV18; JV18-1; MADH2; MADR2; SMAD2; MADH2 gene; MADH7; MADH8; SMAD7; MADH7 gene; Progressive Disease; Kidney Cancer; Kidney Carcinoma; Renal Cancer; Renal carcinoma; Address; DNA Alteration; DNA mutation; Genetic mutation; Sequence Alteration; genomic alteration; DNA Sequence Alteration; Data; Recombinants; Regulatory Affairs; Xenograft Model; xenograft transplant model; xenotransplant model; Preparation; Development; developmental; Cytokeratin-8 Staining Method; CK8; pre-clinical; preclinical; preclinical study; pre-clinical study; vector; age related; age dependent; design; designing; Biodistribution; innovation; innovate; innovative; therapeutic gene; gene therapeutics; gene-based therapeutic; gene-based therapeutics; genes therapeutic; genes therapeutics; adeno-associated viral vector; AAV vector; adeno-associated virus vector; drug testing; drug detection; overexpression; overexpress; cancer cachexia; cancer associated cachexia; cancer induced cachexia; cancer-associated muscle wasting; cancer-induced muscle atrophy; cancer-induced muscle loss; cancer-induced muscle wasting; cancer-related cachexia; tumor-induced cachexia; tumor-induced muscle wasting; FBXO32 gene; ATROGIN1; F-box protein 32; FBXO32; Fbx32; MAFbx; GDF11 gene; BMP11; Bone Morphogenetic Protein 11; GDF11; Growth/Differentiation Factor 11; age-related muscle loss; age associated muscle atrophy; age-associated decline in muscle; age-associated muscle decline; age-associated muscle deterioration; age-associated muscle loss; age-associated muscle wasting; age-related decline in muscle; age-related muscle decline; age-related muscle deterioration; age-related muscle wasting; exercise capacity; preclinical development; pre-clinical development; first-in-human; first in man; Phase I/II Clinical Trial; Phase 1/2 Clinical Trial
