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

Gene Therapy (2025)Cite this article

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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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Data availability

Additional data are available from the corresponding author on reasonable request.

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Acknowledgements

We would like to thank the researchers, physicians and patients for taking part in this study and providing the information included.

Funding

It was not obtained any funding agreements with agencies that may be interested in publishing this article.

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Authors and Affiliations

  1. Department of Neurology, Faculdade de Medicina, Universidade de São Paulo (FMUSP), São Paulo, Brazil

    Clara Gontijo Camelo, Rodrigo Holanda Mendonça, Cristiane Araújo Martins Moreno, Juliana Caires Oliveira Achili Ferreira & Edmar Zanoteli

  2. Hospital Samaritano Higienópolis, São Paulo, Brazil

    Rodrigo Holanda Mendonça

  3. Hospital Pequeno Príncipe, Curitiba, Brazil

    Adriana Banzzatto Ortega

  4. Rarus/Hospital Maria Lucinda, Recife, Brazil

    Vanessa van der Linden

  5. Hospital Israelita Albert Einstein, São Paulo, Brazil

    Rejane Souza Macedo Campos

  6. Hospital de Goiânia, Goiânia, Brazil

    Helio van der Linden

  7. Department of Pediatrics, Faculdade de Medicina, Universidade de Minas Gerais (UFMG), Belo Horizonte, Brazil

    Natalia Spinola Costa da Cunha, Juliana Gurgel-Giannetti & Janaina Monteiro Chaves

  8. Santa Casa de Belo Horizonte, Belo Horizonte, Brazil

    Silvana Maria Carvalho Miranda

  9. Heidelberg University, Medical Faculty Heidelberg, Center for Pediatric and Adolescent Medicine, Department I, Division of Pediatric Neurology and Metabolic Medicine, Heidelberg, Germany

    Andreas Ziegler

Authors
  1. Clara Gontijo Camelo
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  2. Rodrigo Holanda Mendonça
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Contributions

CGC and EZ: Study concept, acquisition and analysis of data, literature review, and initial draft of the paper. RHM: Study concept, acquisition, and analysis of data. CAMM, SMCM and AZ: Analysis of data, and critical revision of manuscript for intellectual content. JC, ABO, CCDL, RdSMC, HVDL, NSCdC, JG-G and JMC: acquisition and analysis of data.

Corresponding author

Correspondence to Clara Gontijo Camelo.

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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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Camelo, C.G., Mendonça, R.H., Moreno, C.A.M. et al. Thrombotic microangiopathy following gene therapy for 5q-spinal muscular atrophy. Gene Ther (2025). https://doi.org/10.1038/s41434-025-00545-6

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