Discovering Novel Therapeutics for Myotonic Dystrophy Type 1 (DM1)

点击翻译按钮获取中文摘要

Muscular dystrophies are a diverse collection of ~30 genetic diseases that involve progressive muscle weakness and are often fatal. The most common adult muscular dystrophy is Myotonic Dystrophy Type I (DM1 or MMD1), which affects between 1:8,000 and 1:22,000 people, causing serious disabilities and a shortened lifespan. DM1 results from expanded CUG repeats in 3’-UTR (untranslated region) of the DMPK gene and is characterized by the accumulation of toxic RNA molecules. There are no effective treatments for DM1 in large part due to the limitations of traditional drug screening assays. Genma Biosciences (Genma Bio) has developed paradigm-shifting assays to enable its long-term goal of producing a lead DM1 therapeutic compound ready for clinical trials. In this proposal, Genma Bio will further develop and validate its high-throughput whole-animal C. elegans screening technology and merge it with cutting-edge automated movement monitoring in an intact, living DM1 disease model. Using a whole-animal model allows Genma Bio to identify small molecule hits in which DM1 defects are corrected at the point of origin of the disease, namely RNA toxicity occurring in its native context. Hits should include classes of compounds that are only accessible in an intact organism such as those involved in inter-tissue signaling. In addition, by assaying for the restoration of DM1 phenotypes such as movement, Genma Bio does not assume a specific target and can identify drug candidates acting by novel mechanisms potentially applicable to multiple related disorders. Specifically, DM1 drugs identified using these assays may also be effective against other myotonic dystrophies and the ~20 diseases caused by RNA repeat expansions including Spinocerebellar Ataxias types 8, 10, 12 and 36, Fragile X Syndrome, and Amyotrophic Lateral Sclerosis (ALS). The cumulative result of the Genma Bio approach will be a broader and more comprehensive set of high-quality compounds than would be identified through traditional screen approaches and that have optimal in vivo efficacy and favorable drug properties (low toxicity, good bioavailability). There are 2 specific aims: Aim 1: Modify the movement assays to be compatible with the C. elegans DM1 HTS platform. Aim 2: Perform a proof-of-principle screen using 10,000 known bioactive compounds to identify small molecules that rescue DM1 defects. Importantly, success here will result in a drug discovery pipeline generalizable to a variety of muscular dystrophies. This Phase I proposal will provide the foundation of a Phase II SBIR which will include a larger-scale screen and follow-up on prioritizing compounds, mammalian testing, and elucidation of the mechanism of action.