Introduction
Duchenne muscular dystrophy (DMD) is a rare X-linked genetic disorder that results from out of frame mutations in the dystrophin gene. The incidence is believed to be 1 in 5,000 male births 1; however, it is now appreciated that female carriers can also manifest the disease. Dystrophin is a critical protein involved in membrane stabilization by anchoring the inner surface of the sarcolemma to F-actin 2. Disruption of the protein results in both progressive skeletal muscle disease as well as a cardiomyopathy. Modern advancements in respiratory therapies have significantly impacted survival with the cardiomyopathy now considered the leading cause of mortality. While the focus historically has been largely on the impact of therapies on skeletal muscle disease, with the advent of emerging molecular and genetic therapies, clinical trials will need to focus on understanding the impact not only on skeletal muscle function but also on cardiopulmonary disease. The failure of many trials to include cardiac and even sometimes respiratory endpoints has impaired our ability to understand the impact of contemporary therapies on the heart and lungs.
If there is not a family history of the disease, children tend to be diagnosed within the first few years of life when they fail to meet gross motor milestones. Clinical cardiac dysfunction tends not to occur later in the disease, but we now know that the myocardium is impacted early in the disease. In fact, EGC’s taken in the newborn and young child are often abnormal and show evidence of left ventricular hypertrophy. Furthermore, cardiac magnetic resonance imaging (CMR) has allowed us an important window into what is occurring in the heart of the young DMD patient. Abnormalities of myocardial strain are noted before the onset of the development of myocardial fibrosis or declining function. Traditional heart failure medications are the only avenue of treatment at this time. Left ventricular assist devices (LVAD) and cardiac transplantation are treatments that have been utilized in isolated instances.
Early reports of new advances in gene therapy appear promising for delaying loss of ambulation and improving quality of life in children with DMD 3. The impact of gene therapy on cardiopulmonary outcomes, howver, is unknown. Herein we review preclinical data regarding the potential for gene therapy to ameliorate DMD-associated cardiomyopathy and review the landscape of current DMD gene therapy efforts, including gene replacement, gene modulation, and gene editing. Because even less is known about the effects of gene therapy on lung function, we focus our discussion on various pulmonary endpoints that should be considered as potential outcome measures in future trials of DMD gene therapy.