Abstract Rationale Duchenne muscular dystrophy (DMD) is a progressive X-linked neuromuscular disease caused by loss of function mutations in the dystrophin gene, leading to absence of dystrophin, and consequently muscle degeneration, loss of ambulation, cardiomyopathy and respiratory failure. Delandistrogene-moxeparvovec is an Adeno-Associated-Virus gene therapy (GT) approved for the treatment of patients with DMD. To date, there is limited data regarding its impact on neuromotor and cardiopulmonary function. Cardiopulmonary exercise testing (CPET) remains the gold standard for quantification of aerobic fitness, as it provides simultaneous assessment of the adequacy of cardiac, ventilatory and muscular systems during exercise. This is the first study to characterize the cardiorespiratory responses before and after GT. Methods This is a prospective study of participants with DMD who received delandistrogene-moxeparvovec, compared to untreated controls with DMD. Participants underwent stationary cycling CPET from rest to peak-effort before and after GT at 3-month intervals for the first year after treatment. Results Three individuals with DMD (median age: 11.8 years, range 6.9 to 20.9) were included, one ambulatory, two non-ambulatory, with a median BMI of 21 Kg/m2 (range 14.7-26) at baseline. All participants were on a stable dose of corticosteroids before GT and were off of additional steroids required for GT administration ten weeks after infusion. Three DMD ambulatory controls were included (median age: 12 years, range 8 to 17), median BMI 17 Kg/m2 (range 16-21). After 6-months, peak VO2 increased in all three individuals post-GT dosing (538 + 105 to 658 + 63 ml/min), an average 22% change from baseline, whereas there was no change in the untreated (1,036 + 27 to 1,092 + 33 ml/min) DMD cohort. Similarly, peak power (Figure 1) increased from 12.3 + 7.5 to 15.3 + 8.5 watts) post-dosing, and no change in the untreated cohort (30 + 14 to 30 + 14 watts). One participant underwent testing one year after GT, and demonstrated increased peak VO2 (60%) and power (25%) compared to baseline. In contrast, the untreated cohort had a reduction in peak VO2 (-5%) and work (-18%). In addition, we compared the submaximal exercise response in heart rate (HR) and minute ventilation (VE) in two of the treated individuals. Mean HR decreased from 111 bpm to 98 bpm. Conclusion Overall, these findings suggest modest improvements in cardiorespiratory fitness six months to a year following delandistrogene-moxeparvovec administration. These preliminary data warrant continued testing of the impact of gene-therapy on this population. This abstract is funded by: None
Garcia et al. (Fri,) studied this question.