Clinical and laboratory profile of thrombotic microangiopathy following gene therapy for 5q-spinal muscular atrophy in Brazil

Background: Spinal muscular atrophy linked to chromosome 5 (SMA-5q) is a progressive genetic disease caused by deletions or disease-causing variants in the survival motor neuron 1 (SMN1) gene. Onasemnogene abeparvovec is the first gene replacement therapy (GT) approved to treat SMA-5q. SMN1 gene transfer therapy through AAV9 aims to restore normal levels of functional SMN protein. More recently, new safety concerns have arisen, such as hepatotoxicity, thrombotic microangiopathy (TMA), and prolonged use of corticosteroids, underscoring the importance of continuous post-marketing drug safety monitoring. Objective: This study aimed to show the frequency of TMA in patients with SMA-5q treated with onasemnogene abeparvovec in a large multicenter Brazilian cohort and to describe the clinical and laboratory profile. Methods: This retrospective multicenter observational study evaluated all patients who developed TMA following treatment with onasemnogene abeparvovec for SMA-5q across Brazil from October 2020 to January 2024. Data were collected from medical records and from results presented at conferences (OPHELIA study). Results: Among 150 patients with SMA-5q treated in Brazil from October 2020 to January 2024, seven developed TMA. Six patients were type 1 SMA-5q, and one type 2 SMA-5q. The average age at the time of gene therapy administration was 20.8 months (range: 12 - 37 months), with an average weight of 11.4kg (range: 8.0 - 16.7kg). Notably, only one patient had a documented infection before gene therapy. No patient had received a vaccine within one month before treatment. All patients had antibody titers ≤1:50 before infusion. Patients exhibited the first symptoms of TMA between the first and second week post-infusion (mean 7.8 - range: 6-10 days). Thrombocytopenia in all patients was severe, with values below 50,000 (mean 17,000 - range: 5,000 to 31,000). Six patients exhibited both proteinuria and hypertension, and three experienced oliguria. Additionally, six patients showed increased creatinine levels, indicating signs of acute kidney injury. Five patients required treatment for TMA; two underwent plasmapheresis, and three patients had an increase in the corticosteroid dose to 2mg/kg/day. One patient treated with plasmapheresis developed hematuria, kidney and liver failure, and died. All other patients recovered after TMA. The occurrence of TMA was associated with prolonged corticosteroid use (mean 194 days - range: 70-390). No patient received Eculizumab or any other immunomodulator. Conclusion: TMA is a severe life-threatening side effect. Early identification and appropriate treatment are essential for a positive outcome.