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Translational Research for Muscular Dystrophy

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Technical Report,01 May 2011,30 Apr 2015

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The Jackson Laboratory Bar Harbor United States

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The overall goal of this work is to increase the availability of critical mouse models of human muscular dystrophy MD for both hypothesis testing and preclinical therapy development. Our multidisciplinary team from The Jackson Laboratory JAX and the Childrens National Medical Center CNMC has expertise in MD, repository management, mouse models, and preclinical testing. Over the course of this funding, Drs. Lutz and Cox at JAX have added 15 new strains to the MD Repository Aim1 to leverage JAXs considerable expertise and infrastructure to maintain and distribute MD mouse resources to the scientific community. In Aim 2 we have completed gene targeting of dystrophin transgenes into DBA2J ES cell lines and have achieved germline transmission fro each line. These novel DMD transgenic mice, which model patients receiving successful exonskipping therapies, will be crossed to mutant D2.B10mdx to score for phenotypic rescue of each mutant and WT line to compare the functionality of resulting dystrophin molecules containing inframe deletions that are expected to arise by successful treatment of patient mutations. In Aim 3, we have completed generation of a DBA2J congenic mdx strain that appears to better model the symptoms of the human disease. Moving the mdx mutation onto different genetic backgrounds has shown the power of genetic variation among inbred strains to alter the disease onset and progression in order to improve the preclinical efficacy. In Aim4, Dr. Nagaraju at CNMC has performed a baseline phenotypic analysis of our new D2.B10mdx model and we have combined the analysis from JAX and CNMC into a manuscript, currently under revision at Human Molecular Genetics, detailing the advantages of this new model for preclinical testing. Our DMD repository has greatly expand the accessibility and availability of mouse model resources for MD translational research and therapeutic development.

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