Background: Duchenne muscular dystrophy (DMD) patients treated with adeno-associated virus (AAV)–based gene therapy (delandistrogene moxeparvovec, Elevidys) are at increased risk for treatment-related liver injury, particularly those who are older, have higher body weight, and are in late ambulatory or non-ambulatory stages. Emerging clinical experience suggests that immune-mediated mechanisms contribute to hepatotoxicity, with variable timing and severity.
Methods & objectives: Based on observed post–gene therapy liver injury patterns in our institution and reported fatalities in older, non-ambulant patients, we hypothesized the presence of two possible immune-mediated phenomena: earlier (<8 weeks) T-cell–mediated liver injury and later (>8 weeks) B-cell–mediated injury. To address both mechanisms, we trialed a pre-treatment immunosuppression strategy using mycophenolate mofetil (CellCept) in addition to increased steroids. Mycophenolate mofetil has inhibitory effects on both B and T cells. This was a clinical decision for two high-risk DMD patients. Mycophenolate mofetil has was started one week prior to delandistrogene moxeparvovec infusion in addition to standard corticosteroid therapy administered after infusion. Liver function tests (LFTs) were obtained at baseline and monitored weekly post-infusion in collaboration with hepatology.
Results: In the first case, gradual elevations in alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) were observed around week 9 post-infusion, prompting an escalation of oral corticosteroids to 2.5 times the standard dose (150 mg daily). LFTs subsequently improved without the need for intravenous methylprednisolone (IVMP) or hospitalization and now at week 12 post-infusion. In the second case, now at week 9 post-infusion, LFTs have remained stable on standard-dose corticosteroids (60 mg daily), with no requirement for steroid escalation or hospital admission.
Conclusion: Pre-treatment immunosuppression with mycophenolate mofetil prior to delandistrogene moxeparvovec infusion may have a role to reduce the severity of immune-mediated liver injury in high-risk DMD patients. By targeting both B-cell and T-cell immune responses, this strategy may decrease the need for hospitalization and intravenous steroid therapy to prevent severe hepatic complications. Further studies in larger cohorts are warranted to define optimal immunosuppressive approaches in this population.