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

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.