Patient-specific responses to SMN2 splice-modifying treatments in spinal muscular atrophy fibroblasts
The availability of three therapies for the neuromuscular disease spinal muscular atrophy (SMA) highlights the need to match patients to the optimal treatment. Two of these treatments (nusinersen and risdiplam) target splicing of <i>SMN2</i>, but treatment outcomes vary from patient to patient. An incomplete understanding of the complex interactions among SMA genetics, SMN protein and mRNA levels, and gene-targeting treatments, limits our ability to explain this variability and identify optimal treatment strategies for individual patients. To address this, we analyzed responses to nusinersen and risdiplam in 45 primary fibroblast cell lines. Pre-treatment <i>SMN2-FL</i>, <i>SMN2Δ7</i> mRNA, and SMN protein levels were influenced by <i>SMN2</i> copy number, age, and sex. After treatment, SMN and mRNA levels were more heterogeneous. In 43% of patients, response to both therapies was similar, but in 57% one treatment led to a significantly higher SMN increase than the other treatment. Younger age, higher <i>SMN2</i> copy number, and higher SMN levels before treatment predicted better <i>in vitro</i> efficacy. These findings showcase patient-derived fibroblasts as a tool for identifying molecular predictors for personalized treatment.
Authors
- Gabriella Viero (ORCID: https://orcid.org/0000-0002-6755-285X)
- Jared W Green
- W. Ludo van der Pol (ORCID: https://orcid.org/0000-0002-8970-2740)
- Maria M Zwartkruis (ORCID: https://orcid.org/0000-0002-8868-7155)
- Thomas H. Gillingwater (ORCID: https://orcid.org/0000-0002-0306-5577)
- Ilaria Signoria (ORCID: https://orcid.org/0000-0002-8314-651X)
- Ewout J. N. Groen (ORCID: https://orcid.org/0000-0002-2330-9444)
- Fay‐Lynn Asselman (ORCID: https://orcid.org/0009-0004-6171-272X)
- Rachel James
- Elena Perenthaler (ORCID: https://orcid.org/0000-0002-8286-0682)
- Renske I. Wadman (ORCID: https://orcid.org/0000-0003-0339-5506)
- Kiterie M. E. Faller (ORCID: https://orcid.org/0000-0002-4525-7059)
- Joris V Kortooms
- Sophie H. Snellen
- Lotte Geerlofs
- Harriet McHale-Owen (ORCID: https://orcid.org/0000-0003-3438-2249)
Institutions
- Mott MacDonald (United Kingdom) (GB)
- University Medical Center Utrecht (NL)
- University of Edinburgh (GB)
Publication Details
- Journal
- Molecular Therapy — Methods & Clinical Development
- Published
- 2024-11-13
- DOI
- https://doi.org/10.1016/j.omtm.2024.101379
- Citations
- 5
- Primary Topic
- Neurogenetic and Muscular Disorders Research
- Type
- article
- Field-Weighted Citation Impact
- 2.19
Funders
- Wellcome Trust
- Motor Neurone Disease Association
- European Commission
- Prinses Beatrix Spierfonds
- Fondazione Cassa Di Risparmio Di Trento E Rovereto
- Stichting Spieren voor Spieren
- Ministero dell'Università e della Ricerca
- Horizon 2020 Framework Programme
- Medical Research Council
- H2020 Marie Skłodowska-Curie Actions