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.
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.
|Wasala, Nalinda B; Shin, Jin-Hong; Lai, Yi et al. (2018) Cardiac-Specific Expression of ?H2-R15 Mini-Dystrophin Normalized All Electrocardiogram Abnormalities and the End-Diastolic Volume in a 23-Month-Old Mouse Model of Duchenne Dilated Cardiomyopathy. Hum Gene Ther 29:737-748|
|Wasala, Nalinda B; Yue, Yongping; Vance, Jenna et al. (2017) Uniform low-level dystrophin expression in the heart partially preserved cardiac function in an aged mouse model of Duchenne cardiomyopathy. J Mol Cell Cardiol 102:45-52|
|Wasala, Nalinda B; Lai, Yi; Shin, Jin-Hong et al. (2016) Genomic removal of a therapeutic mini-dystrophin gene from adult mice elicits a Duchenne muscular dystrophy-like phenotype. Hum Mol Genet 25:2633-2644|
|Yue, Yongping; Wasala, Nalinda B; Bostick, Brian et al. (2016) 100-fold but not 50-fold dystrophin overexpression aggravates electrocardiographic defects in the mdx model of Duchenne muscular dystrophy. Mol Ther Methods Clin Dev 3:16045|
|Yue, Yongping; Binalsheikh, Ibrahim M; Leach, Stacey B et al. (2016) Prospect of gene therapy for cardiomyopathy in hereditary muscular dystrophy. Expert Opin Orphan Drugs 4:169-183|
|Yue, Yongping; Pan, Xiufang; Hakim, Chady H et al. (2015) Safe and bodywide muscle transduction in young adult Duchenne muscular dystrophy dogs with adeno-associated virus. Hum Mol Genet 24:5880-90|
|Duan, Dongsheng; Hakim, Chady H; Ambrosio, Carlos E et al. (2015) Early loss of ambulation is not a representative clinical feature in Duchenne muscular dystrophy dogs: remarks on the article of Barthélémy et al. Dis Model Mech 8:193-4|
|Pan, Xiufang; Yue, Yongping; Zhang, Keqing et al. (2015) AAV-8 is more efficient than AAV-9 in transducing neonatal dog heart. Hum Gene Ther Methods 26:54-61|
|Duan, Dongsheng (2015) Duchenne muscular dystrophy gene therapy in the canine model. Hum Gene Ther Clin Dev 26:57-69|
|McGreevy, Joe W; Hakim, Chady H; McIntosh, Mark A et al. (2015) Animal models of Duchenne muscular dystrophy: from basic mechanisms to gene therapy. Dis Model Mech 8:195-213|
Showing the most recent 10 out of 35 publications