Congenital muscular dystrophy (CMD) is a class of currently untreatable, severe genetic neuromuscular disorders affecting muscle as well as the central nervous system (CNS). The laminin-?2(merosin)-deficient congenital muscular dystrophy (MDC1A) is the most common of them, afflicts 4 in 500,000 children and causes premature death. The purpose of this proposal is to develop an efficient and non-invasive gene delivery method to cross the blood brain barrier (BBB) to the CNS, in addition to the muscle and heart. The method will be tested in a laminin ?2-knockout dyw/dyw mouse model with a mini-agrin gene to replace the lost functions of laminin ?2. Previously we showed that systemic AAV1-mini-agrin delivery greatly improved muscle pathology and extended their lifespan but it failed to deliver to the CNS for improvement of neurological pathology. Recently we found that transient hypothermia greatly enhances AAV delivery into the spinal cord and brain. We have also engineered new chimeric mini-agrin genes with broadened binding substrates and higher affinities. While further optimizing the technology, we propose to use the new enabling tools to test our general hypothesis that revamped mini-agrin gene delivery to muscle, heart and CNS will provide: 1) better and broader therapeutic benefits for muscle and nerve pathologies;and 2) greater improvement in physiological functions and lifespan of the dyw/dyw mouse model. The success of this research plan could be potentially translatable to MDC1A patients and to other neuromuscular diseases as well.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Therapeutic Approaches to Genetic Diseases (TAG)
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Nuckolls, Glen H
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University of North Carolina Chapel Hill
Schools of Pharmacy
Chapel Hill
United States
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