! Myotonic dystrophy type 1 (DM1), the most common form of adult onset muscular dystrophy, is an incurable neuromuscular disorder. Its genetic origin is a triplet (CTG) repeat expansion in the 3'-untranslated region (UTR) of the dystrophia myotonica protein kinase (DMPK) gene. No treatment options exist to delay disease progression. Strong evidence supports a gain-of- function role for the expanded RNA transcript (rCUGexp) and it is considered the toxic agent that causes DM1. The rCUGexp sequesters important proteins, inhibiting their normal function. Chief among these proteins is muscleblind-like protein 1 (MBNL1), a key regulator of alternative splicing. Its sequestration leads to the mis-splicing of >100 pre-mRNAs and many of the symptoms of DM1. The overall goal of this proposal is to discover novel therapeutic approaches and to identify and develop agents that target dCTGexp to inhibit its transcription and rCUGexp, if formed, to liberate sequestered protein. These agents may serve ultimately as new lead therapeutic agents for DM1. This project builds on a series of oligomeric, cell- penetrable agents that target both the DNA and RNA causing DM1. The project will discover and develop optimized oligomers and these will be tested in sophisticated animal models scoring both phenotypic improvements (e.g., cardiac function) and correlating this with target- based activity (levels of relevant spliced RNAs). The speci?c aims of the proposal are: (1) Synthesis and Testing of Discrete, Multi-valent Oligomers, (2) In Vitro and In Vivo Testing of Discrete Oligomers to Obtain Optimal E?cacy, and (3) Development of Muscle-Targeting Oligomers for Enhanced Speci?city and Selectivity. !
. Relevance. Myotonic dystrophy (DM1) afflicts approximately 1 in 8000 adults and is characterized by progressive muscular weakness, cardiac defects, cataracts, and other neuromuscular problems. We propose to develop novel drug discovery approaches for DM1 that involve using small molecules to directly target the aberrantly expanded DNA and inhibit its conversion to the toxic RNA, and to target the toxic RNA to prevent important proteins from binding so that they may perform their normal functions. This approach may serve as a prototype for the treatment of other diseases caused by expanded DNA sequences and their toxic RNA products.
