Incidence, timing, and clinical significance of adverse immune events after gene replacement therapy: A systematic review and meta-analysis

Resumo original em inglês

O que aconteceu

Adeno-associated virus (AAV)-based gene replacement has emerged as a transformative platform for severe genetic disorders, yet immune-mediated adverse events (AEs) pose significant barriers to widespread clinical adoption. We performed a systematic review and meta-analysis of prospective and retrospective studies of AAV gene therapy published between January 2005 and March 2025 (PROSPERO CRD420251046546). Data from 801 studies encompassing 1,972 patients and 2,142 patient-years were pooled to estimate the incidence and clinical impact of immunotoxicity. Random-effects meta-analysis yielded a 30.0% (95% CI, 22.5-38.9; I2 = 83.1%) overall AE rate, including hepatotoxicity in 23.8% (17.4-31.7; I2 = 81.7%), myocarditis in 6.2% (4.6-8.1; I2 = 46%), thrombotic microangiopathy (TMA) in 4.7% (4.4-6.5; I2 = 18.5%), and treatment-related death in 4.7% (3.0-5.3; I2 = 46.1%). Hepatotoxicity and myocarditis were generally mild (97% and 96% non-serious), whereas all TMA episodes carried substantial morbidity. Time course analyses revealed TMA clustered in week 1, myocarditis at week 2, and hepatotoxicity up to 6 months post-infusion. In individual-patient analyses, vector serotype and doses >1 × 1012 vg/kg significantly increased AE risk (OR = 5.59 [1.35-12.2], p = 0.018; OR = 2.31 [1.04-5.53], p = 0.041), whereas combined corticosteroid, anti-CD20, mTOR- and calcineurin inhibitor regimens were protective (OR = 0.67 [0.47-0.96], p = 0.040). At least five cases of TMA, one of myocarditis, and three deaths could not be included in the present analysis because these events were described in company statements. These findings underscore that one-third of AAV recipients experience immunotoxicity, predominantly early and mild, and support proactive immunosuppression and vector optimization to enhance safety.

Resumo publicado sob licença CC BY. A tradução para o português ainda não chegou a este estudo.