Experimental Therapy of Myotonic Dystrophy Myotonic dystrophy type 1 (DM1), the most prevalent form of muscular dystrophy in adults, leads to progressive disability and premature death. No treatment that slows the progress or reverses the symptoms of DM1 is currently available. This disorder is caused by expansion of a CTG repeat in the 3'untranslated region of the DMPK gene, which leads to a novel, RNA-mediated disease process. The focus of this project is on therapeutic development. It appears that RNA-disease mechanisms provide a unique therapetic opportunity in DM1. Viable targets for treatment have been identified, and there are indications that symptoms of DM1 may prove to be surprisingly reversible. Changes in activity of RNA binding proteins are a fundamental aspect of this disease. Muscleblind 1 (MBNL1) protein has a direct interaction with CUG expansion (CUGexp) RNA, which leads to protein sequestration in foci, functional deficiency of MBNL1 in the nucleus, and misregulated alternative splicing for a specific group of pre-mRNAs. Biochemical abnormalities and 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 of this protein are increased, suggesting that stoichiometry of mutant RNA and MBNL1 protein is a key determinant of disease activity. We propose a three-pronged approach to develop treatments for DM1.
Aim 1 employs systemic AAV-mediated gene therapy to increase MBNL1 expression.
This aim builds on previous work showing that local injection of MBNL1 gene therapy vector can reverse muscle defects in a transgenic mouse model of DM1.
Aim 2 proposes to develop a small molecule, orally bioavailable treatment to upregulate MBNL1 protein at a post-transcriptional level.
Aim 3 will employ morpholino antisense oligonucleotides, 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 reversing myotonia and biochemical defects in transgenic mice. We propose to determine if this strategy can prevent or reverse muscle wasting in a conditional mouse model of DM1. Overall, this project will improve our understanding of disease pathogenesis and continue the process of translating recent mechanistic insights into treatments for people with DM1.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZAR1-KM-J)
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University of Rochester
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