Background: Micro-dystrophin gene replacement therapies for Duchenne muscular dystrophy (DMD) have not been thoroughly investigated for their efficacy in preventing or delaying the cardiac manifestations of DMD. Adeno-associated viral serotype 9 (AAV9) has shown to have effective cardiomyocyte transduction following intravenous administration preventing cardiac strain abnormalities and maintaining normal (>55%) ejection fraction (EF) in preclinical models. Here we present long term cardiac imaging resonance imaging (cMRI) data on seven subjects dosed in the Solid Biosciences IGNITE DMD Phase I/II trial using SGT-001, an AAV9 micro-dystrophin therapy.
Methods: Review of cMRI findings of subjects in the IGNITE DMD study at the University of Florida. cMRIs were obtained using a standardized protocol at Baseline and yearly up to Year-5 with a 3T/60cm Siemens Prisma scanner. Images were analyzed using Medis Cardiac Imaging. cMRIs from baseline and yearly up to year 5 after dosing were included. Subjects with 2 or more cMRIs were included.
Results: Seven participants met criteria. All subjects were white males, median age (range) at dosing was 7y (5-14) and had a median BMI (range) of 17.9 (17.6-26.0). One participant was non-ambulant and six were ambulant at the time of dosing. Participant 1-3 received the low-dose of SGT-001 (5E13 vg/kg) and particpants 4-7 received the high-dose (2E14 vg/kg). All were on a daily steroid regimen and under standard cardiac care. Ejection fraction (EF) remained within normal range for subjects 2-7, median 61.8% (51-72). The oldest particpant (14y, Subject 1) exhibited a decreased EF at Year 5 (39%) when compared to his pre-treatment EF (50.9%), however, had near normal left ventricle (LV) endo Global circumferential strain (GCS)% at Year 3 (–16.95). LVEDV was normal in participants 2-7 throughout the duration of the study, median 67.2 mL/m2 (56 -108 mL/m2). Subject 1 showed an increased LVEDV at Year 5 of 118.76 mL/m2 vs. 94.7 mL/m2 pre-treatment.
Conclusion: This is the first study that describes longitudinal cMRI findings in DMD subjects that have received micro-dystrophin gene therapy. We observed that cardiac function was preserved as the individuals age with expected worsening of DMD-related cardiomyopathy. Further studies are needed to better understand the effects of the DMD gene therapy in the heart and carefully quantify the extent of cardiac gene transfer.