Managing Duchenne muscular dystrophy (DMD) has entered a new era with the approval of delandistrogene moxeparvovec-rokl. However, clinicians must vigilantly monitor for AAV gene therapy hepatotoxicity, a potentially life-threatening complication. While standard protocols utilize high-dose corticosteroids, some patients exhibit a refractory response. Recent clinical evidence suggests that sirolimus offers a viable solution for these difficult cases.

A recent case series involving four male patients aged 5 to 16 highlighted the subacute nature of liver inflammation. These patients developed significant hepatic enzyme elevations five to seven weeks after receiving the gene therapy. Despite receiving chronic corticosteroids prior to treatment, the children showed persistent laboratory abnormalities. Consequently, the medical team introduced oral sirolimus to modulate T-cell activity more effectively.

Addressing AAV Gene Therapy Hepatotoxicity with Sirolimus

The introduction of sirolimus produced a remarkable improvement in hepatic markers. Within two to four weeks, gamma-glutamyl transferase normalized and transaminase levels dropped significantly. Clinicians maintained trough levels between 3 and 7 ng/ml, which allowed for a successful weaning of corticosteroids over four to twelve weeks. Notably, no patients experienced serious infections or hepatic synthetic dysfunction during this period.

Furthermore, this management strategy aligns with emerging research into mTOR inhibitors for immune-mediated complications. By targeting T-cell proliferation, sirolimus provides a more specific immunomodulatory effect than broad-spectrum steroids. Therefore, this case series supports using sirolimus as a secondary agent in the safety protocol for AAV-mediated therapies.

What are the signs of liver injury after AAV gene therapy?

Common signs include elevated liver enzymes like ALT and AST, which usually occur within the first few months. Patients may also experience nausea, vomiting, or yellowing of the skin and eyes.

Why is sirolimus used in steroid-refractory cases?

Sirolimus acts as an mTOR inhibitor, specifically targeting T-cell pathways. This provides a more focused immunosuppressive effect when standard corticosteroids fail to control the inflammatory response against the AAV vector.

Disclaimer: This content is for informational and educational purposes only... Refer to the latest local and national guidelines for clinical practice.

References

Leon-Astudillo C et al. Sirolimus for the treatment of steroid-refractory hepatotoxicity following AAV gene therapy in patients with Duchenne muscular dystrophy. J Neuromuscul Dis. 2026 Mar 19. doi: 10.1177/22143602261424971. PMID: 41854298.

Sarepta Therapeutics. Elevidys (delandistrogene moxeparvovec-rokl) [Prescribing Information]. 2025.

FDA. FDA Approves New Safety Warning and Revised Indication for ELEVIDYS. 2025.