Inhibitors of MBNL1 - poly(CUG)binding

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DESCRIPTION (provided by applicant): Myotonic dystrophy type 1 (DM1) is a dominantly inherited disorder that causes progressive disability and premature death. DM1 is the most common form of muscular dystrophy in most referral centers in North America and Europe. No treatment that prevents or slows the progression of DM1 has been identified. The genetic basis of DM1 is an expansion of CTG repeats in the 3' untranslated region of DMPK, a gene encoding a protein kinase. Because the expanded repeat is unstable in germline and somatic cells, and tends to grow larger over time, most individuals with DM1 have several thousand CTG repeats at the DM1 locus in skeletal and cardiac muscle cells. These very large repeat expansions give rise to an unusual RNA dominant disease process in which transcripts from the mutant allele, which contain an expanded CUG repeat (CUGexp), accumulate in the nucleus and interfere with RNA processing for a specific group of genes, thus generating symptoms of DM1. The mechanism for this RNA gain-of-function involves, at least in part, the sequestration by CUGexp RNA of splicing factors in the Muscle blind-like (MBNL) family. MBNL proteins bind to expanded CUGexp RNA with high affinity, forming high molecular weight complexes in the nucleus (ribonuclear foci), and resulting in loss of MBNL function. Recently we have found that oligonucleotide inhibitors of CUGexp-MBNL binding have beneficial effects in a transgenic mouse model of DM1, causing dispersal of ribonuclear foci, restoration of MBNL activity, and improvement of the phenotype. As a first step to developing treatments for DM1, here we propose high throughput screening against the MLSCN's compound collection to identify small molecules that inhibit CUG repeat RNA -MBNL protein binding. PUBLIC HEALTH RELEVANCE: Presently there is no treatment that can prevent muscle weakness in myotonic dystrophy, or that improves the strength of muscles that have already become weak. Recent studies suggest that myotonic dystrophy is caused, at least in part, by a harmful interaction between RNA and protein. The goal of this project is to identify substances that can block this interaction, so that they can be tested and developed as treatment for myotonic dystrophy.