Case Report Raises Questions About Cardiac Microdystrophin Expression, Safety Monitoring With Duchenne Gene Therapy

A Letter to the Editor published in The New England Journal of Medicine raises questions about cardiac microdystrophin expression and the scope of safety monitoring following treatment with delandistrogene moxeparvovec (Elevidys; Sarepta Therapeutics), an adeno-associated virus (AAV) vector-based gene therapy for Duchenne muscular dystrophy (DMD).¹

Investigators described the clinical course of a 17-year-old patient with DMD who developed acute and delayed cardiotoxic effects after receiving delandistrogene moxeparvovec. Analyses of endomyocardial and skeletal-muscle biopsy specimens obtained as part of the patient’s clinical care additionally provided an opportunity to characterize microdystrophin expression in human cardiac and skeletal muscle.

The patient developed myocarditis with symptomatic atrial fibrillation and mild thrombotic microangiopathy 2 days after vector infusion. Recurrent elevations in troponin I levels and worsening cardiac function were subsequently observed on day 42, prompting treatment with intravenous methylprednisolone. Endomyocardial and biceps-muscle biopsies were performed 44 days after administration of the gene therapy.

The authors noted that the endomyocardial biopsy appeared unremarkable, although the specimen was obtained after the patient had received substantial glucocorticoid treatment. The skeletal-muscle biopsy showed dystrophic changes.

Characterizing Microdystrophin Expression in Cardiac Tissue

Molecular analyses of the biopsy specimens showed that the vector copy number was higher in cardiac muscle than in skeletal muscle. However, transcript analysis demonstrated uneven representation across the transgene cassette, with a greater proportion of transcripts derived from the 5′ end than the 3′ end.

The investigators observed findings consistent with incomplete packaging of the transgene cassette, a phenomenon previously described with AAV vectors. Such packaging may limit stable episome formation and expression, potentially leading to the need for higher vector doses to achieve efficacy while increasing the risk of dose-related toxic effects.¹

Spatial analysis of microdystrophin transcripts and protein further demonstrated heterogeneous expression across cardiac and skeletal muscle. Immunofluorescence detected microdystrophin protein in approximately 5% of cardiac muscle fibers and 10% of skeletal-muscle fibers. In the skeletal-muscle fibers expressing microdystrophin, investigators also observed restoration of the dystrophin-glycoprotein complex.

However, Western blot analysis showed microdystrophin levels of less than 1% of normal dystrophin levels in both cardiac and skeletal-muscle specimens. The authors cautioned that these measurements may underestimate steady-state expression because the biopsy specimens were obtained approximately 6 weeks after vector infusion, before stable episome formation would be expected to have occurred.

Potential Implications for Cardiac Safety

The mechanism underlying the patient’s delayed cardiotoxic effects remains uncertain, according to the study authors. They suggested that an adaptive immune response to the AAV capsid may have contributed to the delayed effects.

“The clinical implications of heterogeneous expression are uncertain but may affect long-term efficacy and potentially exacerbate arrhythmogenic risk,” the authors wrote.¹

The findings are notable given the established cardiac involvement of DMD, in which progressive cardiomyopathy is a major contributor to morbidity and mortality. The authors also noted that cardiac microdystrophin expression in humans has remained relatively uncharacterized.

Microdystrophin Production in EMBARK

The findings described in the NEJM letter come in the context of clinical data demonstrating microdystrophin production following treatment with delandistrogene moxeparvovec. In the pivotal phase 3 EMBARK trial, treatment with the gene therapy resulted in mean microdystrophin expression of 34.29% of normal levels at week 12, compared with 0% in the placebo group.²

More recent 2-year EMBARK data demonstrated sustained microdystrophin expression, with mean levels increasing from 34.29% of normal at week 12 to 45.68% at week 64 in biopsy samples from a subset of treated participants.³

These findings provide evidence of sustained microdystrophin expression following treatment, while the current case offers additional tissue-level information about the distribution and heterogeneity of that expression in cardiac and skeletal muscle.

Broader Safety Context and Monitoring

The cardiac findings also add to a broader safety history surrounding delandistrogene moxeparvovec. In November 2025, the FDA added a boxed warning to the therapy's prescribing information for serious liver injury and acute liver failure, including fatal cases, and narrowed the indication to ambulatory patients with DMD aged 4 years and older. The revised labeling also recommends weekly troponin I monitoring for 1 month following treatment.⁴

Earlier in 2025, the European Medicines Agency requested a temporary pause in 3 clinical trials of delandistrogene moxeparvovec following the death of a patient who developed acute liver failure after treatment. Sarepta reported that acute liver injury was a recognized potential adverse effect and that the patient had also experienced a recent cytomegalovirus infection that investigators considered a possible contributing factor.⁵

At the same time, pooled clinical-trial data from patients followed for up to 5 years showed a generally manageable safety profile, although serious treatment-related adverse events included liver abnormalities, rhabdomyolysis, myocarditis, and immune-mediated myositis.

The investigators also outlined broader considerations for the clinical management of patients receiving delandistrogene moxeparvovec.

“This case highlights the need for safety monitoring beyond that recommended on the label,” the investigators wrote.¹ “Our data showed low-level, heterogenous transgene expression in target tissues. An analysis in a larger cohort is required to determine whether these observations are generalizable in patients who have received treatment with delandistrogene moxeparvovec.”

Because the findings come from a single patient, they do not establish whether the cardiac expression patterns or toxic effects are representative of other individuals treated with delandistrogene moxeparvovec.

The case provides new human tissue-level data on cardiac microdystrophin expression following DMD gene therapy while highlighting unresolved questions surrounding transgene packaging, tissue distribution, potential immune-mediated toxicity, and cardiac safety monitoring.

REFERENCES
1. Samelson-Jones B, Martos-Rus C, Yrigollen C, et al. Cardiotoxic Effects and Microdystrophin Expression after Gene Therapy for DMD. N Engl J Med. 2026;395(6):615-617. Doi: 10.1056/NEJMc2518477
2. Sarepta Announces Positive Topline Three-Year EMBARK Results Showing ELEVIDYS Significantly Slows Disease Progression on Key Functional Measures in Ambulatory Duchenne Patients. News release. Sarepta Therapeutics. January 26, 2026. Accessed August 17, 2026. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-announces-positive-topline-three-year-embark-results
3. Mendell JR, Muntoni F, McDonald CM, et al. Two-Year Outcomes Following Delandistrogene Moxeparvovec Treatment in Ambulatory Patients with Duchenne Muscular Dystrophy: Phase 3 EMBARK Trial. Neurol Ther. 2026;15(2):545-559. doi: 10.1007/s40120-025-00879-8.
4.FDA approves new safety warning and revised indication that limits use for Elevidys following reports of fatal liver injury. US Food and Drug Administration. News Release. November 14, 2025. Accessed August 17, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-new-safety-warning-and-revised-indication-limits-use-elevidys-following-reports-fatal
5. FDA investigating deaths due to acute liver failure in non-ambulatory Duchenne muscular dystrophy patients following ELEVIDYS. US Food and Drug Administration. News Release. June 24, 2025. Accessed August 17, 2026. https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/fda-investigating-deaths-due-acute-liver-failure-non-ambulatory-duchenne-muscular-dystrophy-patients