Dados do Trabalho

Título

CLINICAL AND LABORATORY PROFILE OF THROMBOTIC MICROANGIOPATHY FOLLOWING GENE THERAPY FOR 5Q-SPINAL MUSCULAR ATROPHY IN BRAZIL

Introdução

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.

Objetivo

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, genetical and laboratory profile.

Método

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 exome was performed to evaluate an underlying genetic susceptibility.

Resultados

Among 180 patients with SMA-5q treated in Brazil from October 2020 to January 2024, seven(3,8%) 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(R:12-37 months), with an average weight of 11.4 kg(R: 8.0-16.7 kg).Three patients had infections prior to gene therapy. No patient had received a vaccine within one month before treatment. All patients had antibody titers ≤1:50 before infusion.All patients experienced some functional improvement after treatment.Patients exhibited the first symptoms of TMA between the first and second week post-infusion (M 7.8; R:6-10 days).Thrombocytopenia in all patients was severe, with values below 50,000 (mean 17,000 - range: 5,000 to 31,000).6/7 patients exhibited both proteinuria and hypertension, and three patients experienced oliguria. Additionally, 6 out of 7 patients showed increased creatinine levels, indicating signs of acute kidney injury.5/7 patients required treatment for TMA.Two patients underwent plasmapheresis.One of them developed kidney failure and died. 5/7 performed exome and none had pathogenic variants in genes associated with secondary TMA.

Conclusão

TMA is a severe life-threatening side effect.Early identification and appropriate treatment are essential for a positive outcome.Infections prior to infusion are a risk factor

Referências

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Palavras Chave

TMA; SMA; Gene Therapy