The muscular dystrophies, many caused by mutations in genes encoding proteins of the dystrophin complex, are among the most prevalent and devastating human diseases. No cures exist and current treatments that slow muscle degeneration are largely ineffective. The goal of this application is to apply basic knowledge of several muscular dystrophies to developing therapeutic approaches. In project 1, Jeffrey Chamberlain will isolate alternative types of myogenic stem cells, correct the primary genetic lesion in these cells by gene transfer, and explore the use of such cells for transplantation into syngeneic, dystrophic mice. He will generate myogenic stem cells from dystrophic muscle fibroblasts and explore their ability to generate new muscle tissue in vitro and in vivo and explore the therapeutic use of pericytes isolated from dystrophic muscle. In project 2, Stephen Tapscott will expand the cell therapy approach by examining muscle cell transplantation in the canine model of muscular dystrophy. Enhancement of migration and engraftment of transplanted donor cells will be explored by modulating signaling pathways and extracellular matrix components and genetic manipulations. Finally, specific muscle derived cell populations will be compared for their ability to reconstitute canine skeletal muscle in vivo. In project 3, Stephen Hauschka will modify muscle-specific regulatory cassettes to provide high expression in human muscle cultures. Modified cassettes will then be tested in vivo for expression of therapeutic proteins after AAV and Lentiviral delivery to human muscle xenografts in immunodeficient mice. Clonal satellite cell assays and analysis of human muscle fiber regeneration following xenograft injury will determine whether the satellite cell pool has been stably transduced. In project 4, Stanley Froehner will study a new compensatory gene, NPC1, which markedly reduces the severity of the dystrophic phenotype in mdx mouse muscle. The mechanism of NPC1 phenotype amelioration and its applicability to LGMDs will be studied. Two core facilities will serve the participating laboratories.

Public Health Relevance

Our goal is to develop methods that could be used to treat the muscular dystrophies (MDs). Stem cell therapy is a promising approach, but many limitations prevent its implementation at present. Our studies are designed to identify an accessible source of muscle stem cells that could be used for autologous stem cell therapies, and to genetically manipulate those cells to produce the protein missing in common MDs.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Porter, John D
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University of Washington
Schools of Medicine
United States
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Parker, Maura H; Tapscott, Stephen J (2013) Expanding donor muscle-derived cells for transplantation. Curr Protoc Stem Cell Biol Chapter 2:Unit 2C.4
Himeda, Charis L; Tai, Phillip W L; Hauschka, Stephen D (2012) Analysis of muscle gene transcription in cultured skeletal muscle cells. Methods Mol Biol 798:425-43
Tai, Phillip W L; Smith, Catherine L; Angello, John C et al. (2012) Analysis of fiber-type differences in reporter gene expression of ?-gal transgenic muscle. Methods Mol Biol 798:445-59
Goncalves, Manuel A F V; Janssen, Josephine M; Nguyen, Quynh G et al. (2011) Transcription factor rational design improves directed differentiation of human mesenchymal stem cells into skeletal myocytes. Mol Ther 19:1331-41
Suga, Tomohiro; Kimura, En; Morioka, Yuka et al. (2011) Muscle fiber type-predominant promoter activity in lentiviral-mediated transgenic mouse. PLoS One 6:e16908
Banks, Glen B; Combs, Ariana C; Chamberlain, Jeffrey S (2010) Sequencing protocols to genotype mdx, mdx(4cv), and mdx(5cv) mice. Muscle Nerve 42:268-70
Kimura, En; Li, Sheng; Gregorevic, Paul et al. (2010) Dystrophin delivery to muscles of mdx mice using lentiviral vectors leads to myogenic progenitor targeting and stable gene expression. Mol Ther 18:206-13
Hall, John K; Banks, Glen B; Chamberlain, Jeffrey S et al. (2010) Prevention of muscle aging by myofiber-associated satellite cell transplantation. Sci Transl Med 2:57ra83
Himeda, Charis L; Ranish, Jeffrey A; Pearson, Richard C M et al. (2010) KLF3 regulates muscle-specific gene expression and synergizes with serum response factor on KLF binding sites. Mol Cell Biol 30:3430-43
Banks, Glen B; Chamberlain, Jeffrey S; Froehner, Stanley C (2009) Truncated dystrophins can influence neuromuscular synapse structure. Mol Cell Neurosci 40:433-41

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