Experimental Therapy of Myotonic DystrophyMyotonic dystrophy type 1 (DM1), the most prevalent form of muscular dystrophy in adults, leads toprogressive disability and premature death. No treatment that slows the progress or reverses the symptomsof DM1 is currently available. This disorder is caused by expansion of a CTG repeat in the 3' untranslatedregion of the DMPK gene, which leads to a novel, RNA-mediated disease process. The focus of this projectis on therapeutic development. It appears that RNA-disease mechanisms provide a unique therapeticopportunity in DM1. Viable targets for treatment have been identified, and there are indications thatsymptoms of DM1 may prove to be surprisingly reversible. Changes in activity of RNA binding proteins are afundamental aspect of this disease. Muscleblind 1 (MBNL1) protein has a direct interaction with CUGexpansion (CUGexp) RNA, which leads to protein sequestration in foci, functional deficiency of MBNL1 in thenucleus, and misregulated alternative splicing for a specific group of pre-mRNAs. Biochemical abnormalitiesand physiological defects in mouse models of DM1 are sensitive to levels of MBNL1. In transgenic mice,phenotypes caused by CUGexp RNA are aggravated when MBNL1 is reduced and mitigated when levels ofthis protein are increased, suggesting that stoichiometry of mutant RNA and MBNL1 protein is a keydeterminant of disease activity. We propose a three-pronged approach to develop treatments for DM1.
Aim1 employs systemic AAV-mediated gene therapy to increase MBNL1 expression.
This aim builds onprevious work showing that local injection of MBNL1 gene therapy vector can reverse muscle defects in atransgenic mouse model of DM1.
Aim 2 proposes to develop a small molecule, orally bioavailable treatmentto upregulate MBNL1 protein at a post-transcriptional level.
Aim 3 will employ morpholino antisenseoligonucleotides, consisting of CAG repeats, to hybridize CUGexp RNA and displace sequestered proteins.
This aim builds on preliminary studies indicating that this material is well tolerated and effective for reversingmyotonia and biochemical defects in transgenic mice. We propose to determine if this strategy can preventor reverse muscle wasting in a conditional mouse model of DM1. Overall, this project will improve ourunderstanding of disease pathogenesis and continue the process of translating recent mechanistic insightsinto treatments for people with DM1.
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