Duchenne Muscular Dystrophy (DMD) in both humans and dogs is a fatal, X-linked, recessive muscle disease caused by lack of dystrophin due to deletions or mutations in the dystrophin gene. Adeno- associated virus (AAV)-mediated delivery of a shortened (micro) dystrophin gene to skeletal muscle has been successful in mice, however, recent studies indicate that the efficacy of AAV-mediated therapies might be limited by an immune response to viral capsid proteins in humans. Similarly, we have demonstrated robust cellular immune responses to AAV capsid proteins following direct intramuscular injection of AAV vectors in wild type and cxmd (canine X-linked muscular dystrophy) dogs. Fortunately, we have demonstrated that this immune response can be averted by a brief course of immunosuppression. Furthermore, we have shown that previously used AAV vectors can transfer and express the AAV cap gene at low levels, and have found a method to prevent such transfer. Our results to date indicate that this and other vector modifications can reduce AAV vector immunogenicity in dogs. The broad, long-term objective of this project is to develop AAV-mediated gene therapy strategies in cxmd dogs that can be applied to human patients with DMD. We are now ready to test an optimized AAV vector that expresses micro- dystrophin in humans. In this revision application, we are requesting funding for production of the clinical-grade AAV vector and for costs associated with regulatory approval required for clinical studies. Drs. Miller and Halbert at the FHCRC, who have participated in previous clinical trials of gene therapy and have the required vector production and regulatory approval experience, will spearhead these efforts. We plan to carry out initial clinical trials in parallel with additional studies in dogs, conducted as part of the parent application, to refine and improve techniques for effective treatment of DMD in humans.

Public Health Relevance

The importance of this revision application is that it will provide funding to make clinical-grade AAV vectors designed to treat Duchenne muscular dystrophy (DMD), and to obtain regulatory approval for testing of these vectors in humans. Our current studies are at the point where we are ready to test an optimized AAV vector in humans, and funding for clinical vector production and for regulatory approval is critically required to pursue our goal of effective gene therapy for human DMD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
3R01AR056949-03S1A1
Application #
8304799
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Nuckolls, Glen H
Project Start
2008-12-01
Project End
2013-06-30
Budget Start
2011-07-20
Budget End
2012-06-30
Support Year
3
Fiscal Year
2012
Total Cost
$109,120
Indirect Cost
$47,120
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
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Kerwin, William S; Naumova, Anna; Storb, Rainer et al. (2013) Mapping contrast agent uptake and retention in MRI studies of myocardial perfusion: case control study of dogs with Duchenne muscular dystrophy. Int J Cardiovasc Imaging 29:819-26
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Wang, Zejing; Tapscott, Stephen J; Storb, Rainer (2011) Local gene delivery and methods to control immune responses in muscles of normal and dystrophic dogs. Methods Mol Biol 709:265-75
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