Duchenne muscular dystrophy (DMD) is a progressive, lethal, muscle wasting disease that affects 1 in 3500 newborn males. Although tremendous progress has been made in advancing cures for the disease through gene therapeutic approaches, clinical application of gene therapies remains a distant goal and strategies for ameliorating the pathology are needed to reduce disease severity until a cure is established. DMD muscle and mdx mouse muscle experience extensive inflammation that is believed to accelerate DMD pathology. However, recent discoveries have shown that the inflammatory infiltrate is complex and that some immune cells promote muscle regeneration. The ability of macrophages to modulate injury and repair of dystrophic muscles suggests that experimental manipulations of macrophage function could provide a strategy to influence DMD pathology. Furthermore, macrophages could provide a means for the targeted selective delivery of therapeutic molecules rapidly to sites where the disease is most active. The overall objective of this investigation is to use the mdx mouse model of DMD to examine whether immune cells can function as vectors to deliver therapeutic molecules that reduce the pathology of DMD. Our experimental strategy is to suppress the immune compartment of mdx mice by myeloablative irradiation, then transplant bone marrow cells obtained from mice expressing therapeutic transgenes or wild-type and then assay for effects on the mdx muscle pathology and function. The findings of this investigation will provide new insights into a novel mechanism for the delivery of gene therapy to dystrophic muscle and provide the foundation for new therapeutic strategies for addressing DMD, a significant health problem.

Public Health Relevance

Duchenne muscular dystrophy (DMD) is an inherited, lethal disorder affecting 1 in 3,500 males that is caused by a mutation of the dystrophin gene. DMD involves widespread muscle death and an immune response to injured muscle that exacerbates muscle degeneration. The current study will test novel therapeutic strategies for the targeted delivery of therapeutic molecules to dystrophic muscle to reduce the pathology of DMD.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1)
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Boyce, Amanda T
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University of California Los Angeles
Schools of Arts and Sciences
Los Angeles
United States
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Wehling-Henricks, Michelle; Li, Zhenzhi; Lindsey, Catherine et al. (2016) Klotho gene silencing promotes pathology in the mdx mouse model of Duchenne muscular dystrophy. Hum Mol Genet 25:2465-2482