rAAVrh74.MCK.GALGT2 Protects against Loss of Hemodynamic Function in the Aging mdx Mouse Heart

Area of Science:

• Biomedical research
• Gene therapy
• Cardiovascular medicine

Background:

• Dilated cardiomyopathy is a major cause of death in Duchenne muscular dystrophy (DMD) patients.
• Gene therapies for DMD need to address both skeletal and cardiac muscle dysfunction.
• Previous studies demonstrated GALGT2's efficacy in preventing skeletal muscle damage in mdx mice.

Purpose of the Study:

• To investigate the efficacy of rAAVrh74.MCK.GALGT2 gene therapy in preventing cardiac dysfunction in mdx mouse models of DMD.
• To assess the impact of GALGT2 gene therapy on cardiac function, remodeling, and molecular markers in a dystrophin-deficient heart.

Main Methods:

• Treatment of mdx mice with rAAVrh74.MCK.GALGT2 at different ages (neonatal and 2 months).
• Assessment of hemodynamic function, left ventricular remodeling, and fibrotic gene markers.
• Evaluation of cardiac output, stroke volume, and α-dystroglycan glycosylation.
• Measurement of utrophin protein expression.

Main Results:

• Neonatal treatment did not impair hemodynamic function at 3 months and prevented early cardiac remodeling and fibrosis.
• Intravenous treatment at 2 months significantly improved stroke volume and cardiac output in aged mdx mice.
• Treatment correlated with enhanced CT glycan glycosylation of α-dystroglycan and increased utrophin levels.

Conclusions:

• GALGT2 overexpression via rAAVrh74.MCK.GALGT2 gene therapy effectively inhibits cardiac dysfunction in dystrophin-deficient hearts.
• This gene therapy demonstrates potential for dual benefit in both cardiac and skeletal muscles for DMD patients.
• These findings represent the first evidence of GALGT2's therapeutic effect on the dystrophic heart.