Prospect of gene therapy for cardiomyopathy in hereditary muscular dystrophy

abstract

Introduction: Cardiac involvement is a common feature in muscular dystrophies. It presents as heart failure and/or arrhythmia. Traditionally, dystrophic cardiomyopathy is treated with symptom-relieving medications. Identification of disease-causing genes and investigation on pathogenic mechanisms have opened new opportunities to treat dystrophic cardiomyopathy with gene therapy. Replacing/repairing the mutated gene and/or targeting the pathogenic process/mechanisms using alternative genes may attenuate heart disease in muscular dystrophies.

Areas covered: Duchenne muscular dystrophy is the most common muscular dystrophy. Duchenne cardiomyopathy has been the primary focus of ongoing dystrophic cardiomyopathy gene therapy studies. Here, we use Duchenne cardiomyopathy gene therapy to showcase recent developments and to outline the path forward. We also discuss gene therapy status for cardiomyopathy associated with limb-girdle and congenital muscular dystrophies, and myotonic dystrophy.

Expert opinion: Gene therapy for dystrophic cardiomyopathy has taken a slow but steady path forward. Preclinical studies over the last decades have addressed many fundamental questions. Adeno-associated virus-mediated gene therapy has significantly improved the outcomes in rodent models of Duchenne and limb-girdle muscular dystrophies. Validation of these encouraging results in large animal models will pave the way for future human trials.

Keywords:

• AAV
• adeno-associated virus
• gene therapy
• cardiomyopathy
• Duchenne muscular dystrophy
• DMD
• dystrophin
• capsid engineering
• vector
• capsid
• muscular dystrophy
• gene therapy
• heart failure
• limb-girdle muscular dystrophy
• congenital muscular dystrophy
• myotonic dystrophy

Financial and competing interests disclosure

D Duan is a member of the scientific advisory board for Solid GT, a subsidiary of Solid Biosciences. DMD research in the Duan lab is supported by the National Institutes of Health (NS-90634 and HL91883), Department of Defense (MD130014), Muscular Dystrophy Association, Parent Project Muscular Dystrophy, Jesse’s Journey-The Foundation for Gene and Cell Therapy, Hope for Javier and the University of Missouri. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.