Project 1: Dystrophin delivery to muscle via myogenic progenitors (Chamberlain, JS, P.I.)- Skeletal muscles in Duchenne muscular dystrophy (DMD) patients undergo cycles of necrosis and regeneration leading to loss of muscle fibers and replacement with adipose and connective tissue. Regeneration is supported by activation and recruitment of satellite cells, but the regenerative capacity of dystrophic muscles decreases over time due to poorly understood changes in the muscle microenvironment perhaps coupled with the onset of proliferative senescence. Loss of regenerative capacity is a major contributingfactor to decreasing muscle strength, and leads to profound muscle wasting. One approach to treating DMD and other muscle wasting disorders is to identify and/or generate myogenic progenitor/stem cells either from donors or patients, expand them in vitro or in vivo and use these cells to at least partially restore muscle mass and regenerative capacity. However, satellite cell based therapies have so far failed and there is a great need for alternative stem cells with better potential to support muscle regeneration following transplantation. The goals of this project are to isolate and generate alternative stem cells from dystrophic muscles, to correct the genetic lesion in these cells by gene transfer, and to explore autologous transplantation into dystrophic mice. Towards these goals we have developed a robust system for generating lentiviral (LV) vectors that are able to permanently transduce a variety of dividing and non-dividing cells, including myoblasts, satellite cells, fibroblasts, pericytes and mesoangioblasts. LV (and AAV) vectors can also be directly injected into muscles (or blood vessels in the case of AAV) of mice, leading to gene expression in satellite cells and myofibers for the lifespan of a mouse. We have shown that fibroblasts from dystrophic mice can be genetically corrected and modified to form myogenic progenitors after transplantation into mdx hosts. We have also been exploring the isolation and genetic modification of pericytes for autologous cell therapy of muscular dystrophy. We propose to use fibroblasts directly and indirectly via induction of pluripotent stem (iPS) cells, and to compare their efficacy with that of pericytes upon transplantation into mouse models of DMD.

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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University of Washington
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Whitehead, Nicholas P; Kim, Min Jeong; Bible, Kenneth L et al. (2015) A new therapeutic effect of simvastatin revealed by functional improvement in muscular dystrophy. Proc Natl Acad Sci U S A 112:12864-9
Muir, Lindsey A; Nguyen, Quynh G; Hauschka, Stephen D et al. (2014) Engraftment potential of dermal fibroblasts following in vivo myogenic conversion in immunocompetent dystrophic skeletal muscle. Mol Ther Methods Clin Dev 1:14025
Parker, Maura H; Tapscott, Stephen J (2013) Expanding donor muscle-derived cells for transplantation. Curr Protoc Stem Cell Biol Chapter 2:Unit 2C.4
Parker, Maura H; Loretz, Carol; Tyler, Ashlee E et al. (2012) Activation of Notch signaling during ex vivo expansion maintains donor muscle cell engraftment. Stem Cells 30:2212-20
Gantz, Jay A; Palpant, Nathan J; Welikson, Robert E et al. (2012) Targeted genomic integration of a selectable floxed dual fluorescence reporter in human embryonic stem cells. PLoS One 7:e46971
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
Johnson, Eric K; Zhang, Liwen; Adams, Marvin E et al. (2012) Proteomic analysis reveals new cardiac-specific dystrophin-associated proteins. PLoS One 7:e43515
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
Suga, Tomohiro; Kimura, En; Morioka, Yuka et al. (2011) Muscle fiber type-predominant promoter activity in lentiviral-mediated transgenic mouse. PLoS One 6:e16908
Gonçalves, 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

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