Over the past decade, myostatin, a negative regulator of muscle growth, has emerged as a novel therapeutic target for a number of muscle degenerative diseases including Duchene muscular dystrophy (DMD). Inhibition of myostatin promotes muscle growth, and therefore offers an indirect way of compensating muscle degeneration in muscular dystrophies (MD) without directly addressing the specific genetic defects. In a number of mouse MD models, myostatin inhibition has demonstrated substantial efficacies by transgenic technology, delivery of inhibitory proteins/antibodies or AAV gene vectors. However, the therapeutic potential and safety of myostatin inhibition has not been evaluated in large animal MD models, such as the DMD golden retriever muscular dystrophy (GRMD) dogs. We hypothesize that gene delivery of a canine myostatin propeptide, a natural and specific inhibitor of myostatin, by AAV vectors would enhance muscle growth and reduce atrophy, ameliorate dystrophic pathologies and improve muscle functions in the GRMD dogs. In close collaboration with the DMD Canine Model Center at UNC Chapel Hill, we propose to use the GRMD model to study two specific aims: 1) to examine gene expression and therapeutic effects after regional gene delivery in the hindlimbs;2) to evaluate body-wide gene expression, muscle growth and wholebody functional improvement after systemic gene delivery. The success of this project will validate myostatin propeptide in the large animal DMD model and provide an enabling technology for myostatin inhibitor gene therapy for future clinical applications.

Public Health Relevance

This proposal attempts to validate a therapeutic strategy for Duchenne muscular dystrophy by blocking a muscle growth inhibitor, termed myostatin, in a large animal model. Its success will provide an enabling technology for future clinical applications in muscular dystrophies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR056394-05
Application #
8504900
Study Section
Special Emphasis Panel (ZRG1-GTIE-A (01))
Program Officer
Nuckolls, Glen H
Project Start
2009-07-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$300,659
Indirect Cost
$97,511
Name
University of North Carolina Chapel Hill
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Qiao, Chunping; Li, Chengwen; Zhao, Chunxia et al. (2014) K137R mutation on adeno-associated viral capsids had minimal effect on enhancing gene delivery in vivo. Hum Gene Ther Methods 25:33-9
Qiao, Chunping; Yuan, Zhenhua; Li, Jianbin et al. (2012) Single tyrosine mutation in AAV8 and AAV9 capsids is insufficient to enhance gene delivery to skeletal muscle and heart. Hum Gene Ther Methods 23:29-37
Qiao, C; Yuan, Z; Li, J et al. (2011) Liver-specific microRNA-122 target sequences incorporated in AAV vectors efficiently inhibits transgene expression in the liver. Gene Ther 18:403-10
Qiao, Chunping; Zhang, Wei; Yuan, Zhenhua et al. (2010) Adeno-associated virus serotype 6 capsid tyrosine-to-phenylalanine mutations improve gene transfer to skeletal muscle. Hum Gene Ther 21:1343-8