A Novel RNA Therapeutics Platform to Treat Facioscapulohumeral Muscular Dystrophy and other Neuromuscular Disorders

治疗面肩肱型肌营养不良症和其他神经肌肉疾病的新型 RNA 治疗平台

• 批准号: 10155849
• 负责人: Anthony D Saleh
• 金额: $ 37.05万
• 依托单位: MIRECULE, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10155849
• 关键词: ACTA1 gene; Abdomen; Address; Affect; Affinity; Animal Model; Antibodies; Antisense Oligonucleotide Therapy; Antisense Oligonucleotides; Apoptosis; Binding; Biodistribution; Biological Response Modifier Therapy; Blood; Cells; Chemicals; Chemistry; Contracts; Cytoplasm; Data; Development; Disease; Dose; Duchenne muscular dystrophy; Dyes; Elements; Endocytosis; Engineering; Exercise; Face; Facioscapulohumeral Muscular Dystrophy; Genes; Half-Life; Hand Strength; Histopathology; Homeobox; Human; In Vitro; Inflammatory; Inherited; Injections; Label; Lead; Leg; Legal patent; Libraries; Licensing; Maximum Tolerated Dose; Measures; Membrane; Metabolic; Modeling; Monitor; Mus; Muscle; Muscle Cells; Muscle function; Muscular Dystrophies; Mutate; Mutation; Myoblasts; Myopathy; Neuromuscular Diseases; Oligonucleotides; Orphan; Outcome; Oxidative Stress; Pathology; Patients; Peripheral Blood Mononuclear Cell; Phage Display; Phase; Pre-Clinical Model; Process; Proteins; RNA delivery; Rare Diseases; Rattus; Risk; Rodent; Running; Safety; Serum; Shoulder; Small Business Innovation Research Grant; Sum; Symptoms; Technology; Testing; Therapeutic; Tissues; Toxic effect; Toxicology; Transcript; Treatment Efficacy; Xenograft procedure; antibody conjugate; antigen binding; arm; cellular targeting; comparative efficacy; cytokine; design; effective therapy; hydrophilicity; improved; in vivo; innovation; knock-down; lead candidate; manufacturing scale-up; meetings; mouse model; muscle degeneration; muscular dystrophy mouse model; nonhuman primate; novel; pharmacokinetics and pharmacodynamics; receptor; receptor mediated endocytosis; scale up; screening; small molecule; synergism; targeted delivery; therapeutic RNA; therapeutic development; therapeutically effective; transcription factor; uptake

Abstract: In this Fast Track SBIR application miRecule proposes to develop a muscle-specific platform (Muscle-NAVTM) for the delivery of therapeutic oligonucleotide to treat inherited neuromuscular disorders. Over 50 inherited neuromuscular disorders including myopathies, muscular dystrophies, and metabolic muscle disorders have been identified with a monogenic underpinning, resulting from mutations in a single gene. Oligonucleotide therapeutics offer the potential to correct many of these disorders by specifically targeting the mutated disease- causing gene. A major limiting factor that remains is the ability to deliver effective doses of these large hydrophilic molecules into affected muscle cells. Muscle-NAV will be composed of miRecule’s antibody technology directly conjugated to a therapeutic oligonucleotide. The antibody will be targeted to a muscle expressed receptor that induces uptake via endocytosis upon binding. Once endocytosed our novel protein and conjugation chemistry aids in endosomal escape to the cytoplasm. The third most common inherited muscle disorder is facioscapulohumeral muscular dystrophy (FSHD) an orphan indication in the US, with about 20,000 patients. FSHD results from inherited mutations that lead to inappropriate expression of the double homeobox 4 (DUX4) gene. The aberrant expression of DUX4 is severely toxic to muscle tissues, resulting in oxidative stress and apoptosis of muscle cells degrading muscle function. DUX4 is a transcription factor and is not directly “druggable” by traditional small molecules or biologic therapeutics. Several studies have displayed that antisense oligonucleotide (ASO) therapy has the potential to directly repress DUX4, reversing muscle pathology in pre-clinical models. However, a significant hurdle for the development is an effective means of delivery. To validate our Muscle-NAV platform we propose to deliver our (ASO) targeting DUX4 (miRecule candidate MC-DX4) for the treatment of FSHD. In phase 1 of the fast track SBIR, we will first discover novel antibodies for ten receptors with selective muscle expression through phage display screening (AIM 1). We will demonstrate selective delivery and knockdown in muscle cells in vitro (AIM 2). Then screen five conjugates for muscle specific biodistribution, effective delivery and knockdown in an FSHD mouse model, and safety in mice to select a single lead antibody conjugate for Muscle-NAV (AIM 3). In phase 2 of the fast track SBIR, we will optimize scale-up, process development, and CMC release tests for Muscle-NAV and MC-DX4 (AIM 4). We will use this high-quality agent to characterize PK profiles in Non-Human Primates (NHPs), PK/PD profiles in a mouse model of FSHD, and MTD/ Dosing Range/TK profiles in rats (AIM 5). We will also demonstrate the competitive advantage and long- term therapeutic efficacy of MC-DX4 in two mouse models of FSHD (AIM 6). The completion of these studies will create a compelling data package we will use to market co-development and licensing deals for our Muscle- NAV platform, and enable our pre-IND meeting for MC-DX4 as an effective treatment for FSHD.

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