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Gene replacement therapy for spinal muscular atrophy: safety and preliminary efficacy in a Brazilian cohort

Gene Therapy (2024)Cite this article

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Abstract

Spinal muscular atrophy (SMA) is a motor neuron disease associated with progressive muscle weakness, ventilatory failure, and reduced survival. Onasemnogene abeparvovec is the first gene replacement therapy (GT) approved to treat this condition. An observational retrospective study was conducted to assess adverse events and efficacy of GT in SMA patients. Forty-one patients with SMA (58.5% females and 80.1% SMA type 1) were included. The mean age at GT dosing was 18 (±6.4) months. Thirty-six patients (87.8%) were under previous treatment with nusinersen, and 10 (24.4%) continued nusinersen after GT. Mean CHOP-INTEND increased 13 points after 6 months and this finding did not differ between groups according to nusinersen maintenance after GT (p = 0.949). Among SMA type 1 patients, 14 (46.6%) reached the ability to sit alone. Liver transaminases elevation at least two times higher than the upper limit of normal value occurred in 29 (70.7%) patients. Thrombocytopenia occurred in 13 (31.7%) patients, and one presented thrombotic microangiopathy. Older age (>2 years) was associated with more prolonged use of corticosteroids (p = 0.021). GT is effective in SMA patients, combined nusinersen after GT did not appear to add gain in motor function and older age is associated with prolonged corticosteroid use.

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Fig. 1: Violin-plotted* shows mean values of CHOP-INTEND scores after treatment (time 0, 3 months, 6 months, and 12 months after GT).
Fig. 2: Graphic representation of linear correlation HINE-2 x CHOP-INTEND.
Fig. 3: Motor milestones acquisition according to WHO criteria in different SMA types.
Fig. 4: Mean AST and ALT elevations (X times upper normal limits) after GT.
Fig. 5: Total time on prednisolone according to age categories.

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Data availability

The datasets generated and/or analyzed during the current study are not publicly available as they were colected from medical records and are therefore confidential patient information, but are available from the corresponding author upon reasonable request.

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Authors and Affiliations

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

    Rodrigo Holanda Mendonça, Ciro Matsui Jr, Graziela Jorge Polido & Edmar Zanoteli

  2. Hospital Samaritano Higienópolis, São Paulo, Brazil

    Rodrigo Holanda Mendonça & Ciro Matsui Jr

  3. Hospital Pequeno Príncipe, Curitiba, Brazil

    Adriana Banzzatto Ortega

  4. Hospital Maria Lucinda, Recife, Brazil

    Vanessa van der Linden & Marcelo Kerstenetzky

  5. Hospital Infantil Sabará, São Paulo, Brazil

    Luis Fernando Grossklauss

  6. Hospital Moinhos do Vento, Porto Alegre, Brazil

    Elizabeth L. Silveira-Lucas

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Contributions

RHM acquired data, conceived and designed the work, revised and approved the final version of the manuscript. ABO acquired data and revised the manuscript. CMJr acquired data and revised the manuscript. VVL acquired data and revised the manuscript. MK acquired data and revised the manuscript. LFG acquired data and revised the manuscript. ELSL acquired data and revised the manuscript. GJP acquired data and revised the manuscript. EZ designed the work, revised and approved the final version of the manuscript. All authors agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Corresponding author

Correspondence to Rodrigo Holanda Mendonça.

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Competing interests

RHM received fee from Novartis for speaking at symposia and participating in clinical trials. ABO received fee from Novartis for speaking at symposiums. EZ received fee from Novartis for speaking at symposia and participating in clinical trials. Other authors declare no conflicts of interest in relation to this publication.

Ethical approval and consent to participate

The study was approved by the Ethics and Research Committee of the Faculdade de Medicine da Universidade de São Paulo (FMUSP), under reference number 87773118.7.0000.0068. An informed consent was obtained from all subjects for retrospective data collection.

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Mendonça, R.H., Ortega, A.B., Matsui Jr, C. et al. Gene replacement therapy for spinal muscular atrophy: safety and preliminary efficacy in a Brazilian cohort. Gene Ther (2024). https://doi.org/10.1038/s41434-024-00456-y

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