Cardiomyopathy is a leading cause of death in Duchenne muscular dystrophy (DMD), the most common childhood lethal muscle disease. DMD is caused by dystrophin gene mutation and there is currently no cure. Adeno-associated virus (AAV)-mediated micro/mini-dystrophin gene therapy has shown great promise in ameliorating Duchenne skeletal muscle disease. However, we recently found that the abbreviated genes that were developed for treating skeletal muscle disease may not completely fulfill the needs of the heart. Here, we hypothesize that Duchenne cardiomyopathy gene therapy may require a specific dystrophin domain that is missing in the current available micro/minigenes. On reviewing Duchenne cardiomyopathy-related clinical reports over the last 17 years, we identified a putative heart protection domain in the dystrophin gene. In this proposal, we will test whether we can achieve better cardiac rescue by including the putative heart protection domain in the micro/minigenes. Specifically, novel micro/minigenes carrying the putative heart protection domain will be generated. AAV will be used to deliver these micro/minigenes to the heart in the mouse models of Duchenne cardiomyopathy. Comprehensive anatomic, cellular, biochemical, and physiological assays will be used to monitor cardiac rescue. The therapeutic efficacy of new micro/minigenes will also be compared to that of the current micro/minigenes. Our long-term goal is to develop an effective AAV gene therapy to treat patients. A critical step before initiating human trial is preclinical evaluation in the canine DMD model. We hypothesize that AAV gene therapy can ameliorate cardiomyopathy in the golden retriever muscular dystrophy (GRMD) model. The best micro/minigenes identified in the murine model will be delivered to neonatal GRMD puppy by systemic AAV gene transfer. Normal dogs and saline injected GRMD dogs will be included as controls. Progression of the heart disease as well as gene transfer efficiency will be carefully monitored using a comprehensive panel of anatomic, histological, cellular, biochemical, and physiological assays we already developed. Taken together, our study will significantly advance Duchenne cardiomyopathy gene therapy.

Public Health Relevance

Duchenne muscular dystrophy (DMD) is a lethal disease affecting a fairly large population of patients (~one in 3,500 newborn boys). DMD related heart disease significantly reduces the life quality and life span of patients. Here we propose to develop AAV gene therapy to treat Duchenne heart disease. Our findings will pave the way to eventually cure DMD.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL091883-03
Application #
8296177
Study Section
Special Emphasis Panel (ZRG1-MOSS-Q (02))
Program Officer
Kaltman, Jonathan R
Project Start
2010-07-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
3
Fiscal Year
2012
Total Cost
$509,872
Indirect Cost
$135,283
Name
University of Missouri-Columbia
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
153890272
City
Columbia
State
MO
Country
United States
Zip Code
65211
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Kodippili, Kasun; Vince, Lauren; Shin, Jin-Hong et al. (2014) Characterization of 65 epitope-specific dystrophin monoclonal antibodies in canine and murine models of duchenne muscular dystrophy by immunostaining and western blot. PLoS One 9:e88280
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Shin, Jin-Hong; Yue, Yongping; Duan, Dongsheng (2012) Recombinant adeno-associated viral vector production and purification. Methods Mol Biol 798:267-84

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