Duchenne muscular dystrophy (DMD) is an X-linked myopathy caused by mutations or deletions in the dystrophin gene. DMD is a common form of muscular dystrophy, affecting about 1 in every 5000 boys. DMD is a severe disease, causing progressive muscle wasting that leads to loss of ambulation and premature death in affected individuals. Despite having understood the genetic defect in DMD for the past 20 years, no approved therapy exists that has been shown to ultimately alter disease outcome. We have pioneered the development of a novel therapy for DMD based on the overexpression of GALGT2, a gene that encodes a glycosylation enzyme that alters sugars on the skeletal muscle membrane in order to boost the expression of proteins that ameliorate disease. This approach has shown therapeutic efficacy in three different mouse models of muscular dystrophy, including the mdx mouse model for DMD, suggesting that GALGT2 gene therapy may be useful in multiple forms of the disease. GALGT2 overexpression can also protect wild type muscles from injury and may therefore have therapeutic usefulness that extends beyond neuromuscular disorders. In light of these proof of concept studies demonstrating therapeutic efficacy, we have developed gene therapy vectors for use in human clinical trials. Intra-arterial delivery to the hindlimb muscles has shown functional correction in the mdx mouse and sustained expression in the non-human primate. This work has helped move us toward our goal of performing the first GALGT2 gene therapy clinical trial for DMD. The work proposed here will, for the first time, assess the therapeutic efficacy of GALGT2 in protecting the heart muscle, a muscle that greatly affects DMD morbidity and mortality. It will also test a new generation AAV vector that allows high expression in both skeletal muscle and heart to determine if single dose vascular delivery can be used to treat the whole DMD patient. Second, it will test GALGT2 gene therapy in a severe large animal model of DMD. This addresses issues of the scalability of gene therapy to the human and more rigorously tests its therapeutic value. Third, it will describe a new pathway that regulates the expression of endogenous muscle Galgt2 gene expression, opening up new approaches to exploit this important gene for therapy development.

Public Health Relevance

Duchenne muscular dystrophy is a severe, progressive, and ultimately fatal neuromuscular disorder for which there are currently no therapies that ultimately alter disease outcome. The goal of this proposal is to provide proof of concept data for treatment of patients with Duchenne muscular dystrophy with a gene therapy that can be applied in a single treatment via the blood. This approach will utilize a gene therapy with overexpression of a naturally occurring glycosyltransferase gene called GALGT2 in muscle cells. Additional work will focus on understanding the natural control of muscle GALGT2 expression, with the goal of learning how to increase the muscle's natural production of this therapeutic gene.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Cheever, Thomas
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Nationwide Children's Hospital
United States
Zip Code
Xu, Rui; Jia, Ying; Zygmunt, Deborah A et al. (2018) An Isolated Limb Infusion Method Allows for Broad Distribution of rAAVrh74.MCK.GALGT2 to Leg Skeletal Muscles in the Rhesus Macaque. Mol Ther Methods Clin Dev 10:89-104
Cramer, Megan L; Shao, Guohong; Rodino-Klapac, Louise R et al. (2017) Induction of T-Cell Infiltration and Programmed Death Ligand 2 Expression by Adeno-Associated Virus in Rhesus Macaque Skeletal Muscle and Modulation by Prednisone. Hum Gene Ther 28:493-509
Zygmunt, Deborah A; Singhal, Neha; Kim, Mi-Lyang et al. (2017) Deletion of Pofut1 in Mouse Skeletal Myofibers Induces Muscle Aging-Related Phenotypes in cis and in trans. Mol Cell Biol 37:
Zygmunt, Deborah A; Crowe, Kelly E; Flanigan, Kevin M et al. (2017) Comparison of Serum rAAV Serotype-Specific Antibodies in Patients with Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, Inclusion Body Myositis, or GNE Myopathy. Hum Gene Ther 28:737-746
Thomas, Paul J; Xu, Rui; Martin, Paul T (2016) B4GALNT2 (GALGT2) Gene Therapy Reduces Skeletal Muscle Pathology in the FKRP P448L Mouse Model of Limb Girdle Muscular Dystrophy 2I. Am J Pathol 186:2429-48
Crowe, Kelly E; Shao, Guohong; Flanigan, Kevin M et al. (2016) N-terminal ? Dystroglycan (?DG-N): A Potential Serum Biomarker for Duchenne Muscular Dystrophy. J Neuromuscul Dis 3:247-260
Singhal, Neha; Martin, Paul T (2015) A role for Galgt1 in skeletal muscle regeneration. Skelet Muscle 5:3
Xu, Rui; Singhal, Neha; Serinagaoglu, Yelda et al. (2015) Deletion of Galgt2 (B4Galnt2) reduces muscle growth in response to acute injury and increases muscle inflammation and pathology in dystrophin-deficient mice. Am J Pathol 185:2668-84
Chicoine, Louis G; Rodino-Klapac, Louise R; Shao, Guohong et al. (2014) Vascular delivery of rAAVrh74.MCK.GALGT2 to the gastrocnemius muscle of the rhesus macaque stimulates the expression of dystrophin and laminin ?2 surrogates. Mol Ther 22:713-24
Camboni, Marybeth; Wang, Chiou-Miin; Miranda, Carlos et al. (2014) Active and passive immunization strategies based on the SDPM1 peptide demonstrate pre-clinical efficacy in the APPswePSEN1dE9 mouse model for Alzheimer's disease. Neurobiol Dis 62:31-43

Showing the most recent 10 out of 28 publications