Liver enzymes improved after sirolimus was added in four cases of liver toxicity following DMD gene therapy
A case series reports that elevated liver enzymes after AAV gene therapy improved following the addition of sirolimus in four patients with Duchenne muscular dystrophy (DMD). In patients whose laboratory abnormalities had temporarily improved or worsened during high-dose corticosteroid treatment, gamma-glutamyl transferase (GGT) normalized and transaminase levels improved within 2–4 weeks after sirolimus was added. This small, uncontrolled observational report does not establish the efficacy of sirolimus.
The report describes liver toxicity after delandistrogene moxeparvovec-rokl (Elevidys), an adeno-associated virus (AAV)-based gene therapy for DMD. In the abstract’s background, the authors explain that liver toxicity had been observed after this treatment and that, by the time of their report, two cases had progressed to liver failure and death. Those cases are separate from the treatment courses of the four patients described here.
The patients were four boys who developed acute liver inflammation after receiving gene therapy at one academic medical center. They were 5–16 years old and weighed 20.8–56.7 kg; median weight was 32.5 kg. All four had been taking corticosteroids long term for DMD before gene therapy. Three were ambulatory; this is a patient characteristic, not a finding that motor function recovered after sirolimus treatment.
All four developed elevated liver enzymes 5–7 weeks after gene therapy. Clinicians increased corticosteroid doses in response to the laboratory abnormalities, but the values improved only temporarily or worsened. They subsequently added oral sirolimus, primarily for T-cell immunomodulation. The target trough blood concentration was 3–7 ng/mL. Clinical follow-up and repeated laboratory testing were performed, along with cardiac and functional assessments according to the institution’s care procedures.
Within 2–4 weeks of adding sirolimus, GGT normalized and transaminase levels improved. These findings do not mean that all liver enzyme levels returned to normal. Sirolimus was given for 4–12 weeks, during which corticosteroids could be tapered. No hepatic synthetic dysfunction or severe infections were reported in these patients. These are the observed safety findings; they do not mean that no adverse events occurred or that long-term safety was established.
The authors interpreted the clinical course as showing a subacute pattern of liver inflammation emerging weeks after AAV gene therapy and as supporting the potential use of mTOR inhibitors such as sirolimus. However, corticosteroids were used concurrently and there was no comparison group, so the contribution of sirolimus to the improvement cannot be isolated. The stated aim of T-cell immunomodulation also does not mean that this study established the mechanism of liver toxicity or the drug’s pathway of action.
The provided abstract does not give patient-level liver enzyme values, long-term follow-up results, or specific findings from the cardiac and functional assessments. The report offers a lead for studying additional immunomodulatory strategies when liver toxicity does not improve sufficiently with corticosteroids, but it does not establish a standard treatment or demonstrate prevention of liver failure. Further details are available in the PubMed abstract.
BACKGROUND: Adeno-associated virus (AAV)-mediated gene therapy with delandistrogene moxeparvovec-rokl (Elevidys®) is an approved treatment for patients with Duchenne muscular dystrophy (DMD). While generally well tolerated, hepatotoxicity has been observed following its administration, leading to liver failure and death in two reported cases to date. METHODS: This is a case series describing four male patients with DMD, who received delandistrogene moxeparvovec-rokl at a single academic medical center and developed acute liver inflammation. All patients received corticosteroids, with doses increased as abnormalities developed, followed by the addition of oral sirolimus (goal trough: 3-7 ng/ml), which was used primarily for T-cell immunomodulation. Monitoring included close clinical follow up, serial laboratory testing, and cardiac and functional assessments per institutional protocol. RESULTS: The patients were between 5 and 16 years of age with a weight between 20.8 and 56.7 kg, (median: 32.5 kg). Three boys were ambulatory. The four patients were receiving chronic corticosteroids for the treatment of DMD prior to delandistrogene moxeparvovec-rokl administration. All cases developed hepatic enzyme elevations five to seven weeks post-gene therapy. Treatment with high-dose corticosteroids led to transient improvement or worsening of laboratory abnormalities, and initiation of adjunctive sirolimus therapy resulted in normalization of gamma-glutamyl transferase and improvement of transaminases within two to four weeks. The duration of sirolimus treatment ranged from four to twelve weeks, during which corticosteroids were successfully weaned. None of the patients experienced hepatic synthetic dysfunction or serious infections. CONCLUSIONS: These cases illustrate a subacute pattern of liver inflammation following AAV-gene therapy and support the potential role of mTOR inhibitors in managing AAV-related hepatotoxicity.
This study provides a clinical lead for further investigation of adding sirolimus when liver enzyme abnormalities after DMD gene therapy do not improve sufficiently despite increased corticosteroid doses. The rise in liver enzymes 5–7 weeks after gene therapy and the ability to taper corticosteroids during combination treatment may inform what future studies assess. However, four cases cannot establish prevention of liver failure or improved safety of gene therapy overall. Future comparative studies need to assess liver enzyme changes alongside liver function, infections, corticosteroid use, and long-term outcomes.