A major challenge for pharmacological approaches to treating Duchenne muscular dystrophy is targeting the right molecule to the right place at the right time. Even when systemic delivery of a therapeutic molecule has beneficial effects on diseased tissue, off-target effects can produce negative consequences that detract from the clinical use of a particular therapeutic agent. We propose an innovative strategy to exploit the body's own ability to deliver molecules to diseased tissue at sites and times when pathology is most pronounced. We will use bone marrow cells (BMCs) that express a transgene for a therapeutic molecule (LIF) that is driven by a promoter (CD11b) that is highly expressed in activated macrophages and transplant those cells into mice that have muscular dystrophy. Because the onset and severity of muscular dystrophy in mdx mice mirrors the invasion of muscle with myeloid cells that express high levels of CD11b, we anticipate that delivery of therapeutic LIF will track the occurrence and severity of the disease. Thus, we hope to achieve targeted delivery of a therapeutic molecule specifically to diseased tissue "on demand," to minimize negative, off-target effects. If successful, our findings could provide a wholly-new avenue for the treatment of muscular dystrophy. In our proposed investigation, we will explore the use of bone-marrow-derived myeloid cells as vectors for delivery of therapeutic cargo to dystrophic muscle in two aims.
Aim 1. Can transplantation of genetically-modified BMCs provide a mechanism to target therapeutic molecules to dystrophic muscle? We will transplant BMCs from each of three transgenic, donor lines that display LIF transgene expression that ranges from 8- to 131- fold wild-type levels in differentiated leukocytes. Recipient, mdx mice will be assessed for reductions in pathology, shifts in macrophages from a cytolytic to a pro-regenerative phenotype and improved muscle function. We will also assay for the occurrence of negative, off-target effects.
Aim 2. Can non-myeloablative conditioning of recipient mice allow sufficient engraftment of transgenic, donor myeloid cells to provide a rescue from pathology, without negative, off-target effects? In Aim 2, we will test whether the use of pharmacological approaches to non-myeloablative conditioning prior to bone marrow transplantation will yield sufficient targeting of the LIF transgene to muscle and attenuation of muscle pathology without incurring negative, off-target effects.

Public Health Relevance

Duchenne muscular dystrophy is a progressive, lethal, muscle wasting disease with no cure. Our investigation will test whether transplantation of genetically-modified bone marrow cells can be used to deliver therapeutic molecules to dystrophic muscle and reduce pathology.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Exploratory/Developmental Grants (R21)
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Skeletal Muscle and Exercise Physiology Study Section (SMEP)
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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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Villalta, S Armando; Rosenthal, Wendy; Martinez, Leonel et al. (2014) Regulatory T cells suppress muscle inflammation and injury in muscular dystrophy. Sci Transl Med 6:258ra142