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. 2025 Jun 19.
doi: 10.1038/s41434-025-00545-6. Online ahead of print.

Thrombotic microangiopathy following gene therapy for 5q-spinal muscular atrophy

Clara Gontijo Camelo  1 , Rodrigo Holanda Mendonça  2   3 , Cristiane Araújo Martins Moreno  2 , Juliana Caires Oliveira Achili Ferreira  2 , Adriana Banzzatto Ortega  4 , Vanessa van der Linden  5 , Rejane Souza Macedo Campos  6 , Helio van der Linden  7 , Natalia Spinola Costa da Cunha  8 , Juliana Gurgel-Giannetti  8 , Janaina Monteiro Chaves  8 , Silvana Maria Carvalho Miranda  9 , Andreas Ziegler  10 , Edmar Zanoteli  2
Affiliations

Thrombotic microangiopathy following gene therapy for 5q-spinal muscular atrophy

Clara Gontijo Camelo et al. Gene Ther. .

Abstract

Onasemnogene abeparvovec (OA) is the first gene replacement therapy (GT) approved for 5q spinal muscular atrophy (SMA). While effective, it can cause severe side effects, including thrombotic microangiopathy (TMA). The pathophysiology, risk factors, and management of viral-vector-related TMA remain unclear. This study aimed to evaluate TMA frequency among Brazilian patients treated with OA and characterize their clinical and laboratory profiles. This retrospective, multicenter study analyzed 294 Brazilian patients with 5q SMA treated with OA between October 2020 and September 2024, of whom seven (2.4%) developed TMA. The average age at OA administration was 20.4 months, and the average weight was 11.5 kg. Three patients had documented infections before OA administration. TMA symptoms appeared within 6-10 days post-infusion. All patients showed hemolytic anemia, thrombocytopenia, and at least one organ dysfunction. Treatment included plasmapheresis in two cases and increased corticosteroid doses in four cases. One patient died from TMA complications. Whole exome sequencing in five patients identified no pathogenic variants linked to TMA. TMA is a rare but severe complication of OA therapy for SMA. Prompt recognition and management, often with corticosteroids, are crucial for improving outcomes.

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Conflict of interest statement

Competing interests: The authors declare that participated in the development and realization of the article. The authors agree with the time limit for publication. From this date, it becomes public responsibility for its contents. It was not obtained any funding agreements with agencies that may be interested in publishing this article. The article has not been and will not be submitted to other printed or electronic journals. We are also aware that all articles accepted for publication must be published with DOI (digital object identifier). The authors state that there was no conflict of interest during the performance and publication of this article. Ethical approval: The study received approval from the local ethics committee (63660222.5.0000.0068 CAPPESQ), and written informed consent was obtained from the patients’ parents. All methods were performed in accordance with the relevant guidelines and regulations.

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