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Identifying novel response markers for spinal muscular atrophy revealed by targeted proteomics following gene therapy

Gene Therapy (2025)Cite this article

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Abstract

Spinal muscular atrophy (SMA) is a progressive disease that affects motor neurons, with symptoms usually starting in infancy or early childhood. Recent breakthroughs in treatments targeting SMA have improved both lifespan and quality of life for infants and children with the disease. Given the impact of these treatments, it is essential to develop methods for managing treatment-induced changes in disease characteristics. Zolgensma® is the first effective and approved gene therapy for SMA caused by biallelic mutation in the SMN1 gene. In three children with SMA treated with Zolgensma®, neuronal, glial, inflammation, and vascular markers in the plasma exhibited a quicker response, emphasizing their potential as valuable biomarkers of treatment efficacy in clinical trials. We chose the novel Nucleic acid Linked Immuno-Sandwich Assay, to investigate a predefined panel of neuroinflammatory markers in plasma samples collected from SMA patients at baseline and six months after Zolgensma® treatment. We identified a set of novel targets whose levels differed between pre and post Zolgensma® treatment group and that were responsive to treatment. Even though our results warrant validation in larger SMA cohorts and longer follow-up time, they may pave the way for a panel of responsive proteins solidifying biomarker endpoints in SMA clinical trials.

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Fig. 1: Neuronal and glial targets response to Zolgensma® gene therapy.
Fig. 2: Zolgensma® causes changes to inflammatory targets in SMA patients.
Fig. 3: Vascular and other protein changes in pre and post gene therapy.

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Data availability

Data used in this study are available within the article. Additional data supporting the information may be available upon reasonable request.

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Acknowledgements

We thank patients for their donation of biofluids. We acknowledge the support of the coworkers of the Emory Health Sciences Research Building repository for sample storage and preparation. The authors would like to thank two anonymous reviewers for their constructive feedback. We would like to extend our gratitude to the Alamar TAP (technology access program) team for helpful discussion. DCP is supported by MDA DG and LLL CDA. This work was supported by the Children’s Healthcare of Atlanta 1998 Society Grant for SMA gene therapy to SV.

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Authors and Affiliations

  1. Department of Cell Biology, Emory University, Atlanta, 30322, Georgia

    Devesh C. Pant

  2. Departments of Pediatrics and Neurology, Emory University, Atlanta, 30322, Georgia

    Sumit Verma

Authors
  1. Devesh C. Pant
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  2. Sumit Verma
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Contributions

DCP help wrote the draft and SV edited the manuscript. SV planned the study and provided access to the biofluids and de-identified individual participant data.

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Correspondence to Devesh C. Pant or Sumit Verma.

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Pant, D.C., Verma, S. Identifying novel response markers for spinal muscular atrophy revealed by targeted proteomics following gene therapy. Gene Ther (2025). https://doi.org/10.1038/s41434-025-00513-0

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