Discovering Novel Therapeutics for Myotonic Dystrophy Type DM

Muscular dystrophies are a diverse collection of genetic diseases that involve progressive muscle weakness and are often fatal The most common adult muscular dystrophy is Myotonic Dystrophy Type I DM or MMD which affects between and people causing serious disabilities and a shortened lifespan DM results from expanded CUG repeats in UTR untranslated region of the DMPK gene and is characterized by the accumulation of toxic RNA molecules There are no effective treatments for DM 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 DM 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 DM disease model Using a whole animal model allows Genma Bio to identify small molecule hits in which DM 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 DM 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 DM drugs identified using these assays may also be effective against other myotonic dystrophies and the diseases caused by RNA repeat expansions including Spinocerebellar Ataxias types and 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 specific aims Aim Modify the movement assays to be compatible with the C elegans DM HTS platform Aim Perform a proof of principle screen using known bioactive compounds to identify small molecules that rescue DM 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 Muscular Dystrophy Type DM or MMD is the most common form of adult muscular dystrophy affecting approximately to people worldwide There are currently no effective treatments for DM in large part due to the limitations of traditional drug screening approaches This project will develop a unique and potentially paradigm shifting drug screening platform to discover novel DM therapeutics