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 SMN2, but treatment outcomes vary from patient to patient. An incomple...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-12-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050124001955 |
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| author | Ilaria Signoria Maria M. Zwartkruis Lotte Geerlofs Elena Perenthaler Kiterie M.E. Faller Rachel James Harriet McHale-Owen Jared W. Green Joris Kortooms Sophie H. Snellen Fay-Lynn Asselman Thomas H. Gillingwater Gabriella Viero Renske I. Wadman W. Ludo van der Pol Ewout J.N. Groen |
| author_facet | Ilaria Signoria Maria M. Zwartkruis Lotte Geerlofs Elena Perenthaler Kiterie M.E. Faller Rachel James Harriet McHale-Owen Jared W. Green Joris Kortooms Sophie H. Snellen Fay-Lynn Asselman Thomas H. Gillingwater Gabriella Viero Renske I. Wadman W. Ludo van der Pol Ewout J.N. Groen |
| author_sort | Ilaria Signoria |
| collection | DOAJ |
| description | 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 SMN2, 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 SMN2-FL, SMN2Δ7 mRNA, and SMN protein levels were influenced by SMN2 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 SMN2 copy number, and higher SMN levels before treatment predicted better in vitro efficacy. These findings showcase patient-derived fibroblasts as a tool for identifying molecular predictors for personalized treatment. |
| format | Article |
| id | doaj-art-3b66cab32cd941798ce4e53baf5f714a |
| institution | Kabale University |
| issn | 2329-0501 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj-art-3b66cab32cd941798ce4e53baf5f714a2024-11-25T04:41:15ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012024-12-01324101379Patient-specific responses to SMN2 splice-modifying treatments in spinal muscular atrophy fibroblastsIlaria Signoria0Maria M. Zwartkruis1Lotte Geerlofs2Elena Perenthaler3Kiterie M.E. Faller4Rachel James5Harriet McHale-Owen6Jared W. Green7Joris Kortooms8Sophie H. Snellen9Fay-Lynn Asselman10Thomas H. Gillingwater11Gabriella Viero12Renske I. Wadman13W. Ludo van der Pol14Ewout J.N. Groen15Department of Neurology and Neurosurgery, UMC Utrecht Brain Center, Utrecht, the NetherlandsDepartment of Neurology and Neurosurgery, UMC Utrecht Brain Center, Utrecht, the Netherlands; Department of Genetics, University Medical Center Utrecht, Utrecht, the NetherlandsDepartment of Neurology and Neurosurgery, UMC Utrecht Brain Center, Utrecht, the NetherlandsInstitute of Biophysics, CNR Unit, Trento, ItalyEdinburgh Medical School: Biomedical Sciences and Euan MacDonald Centre for Motor Neuron Disease Research, Edinburgh, UK; Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, UKEdinburgh Medical School: Biomedical Sciences and Euan MacDonald Centre for Motor Neuron Disease Research, Edinburgh, UKEdinburgh Medical School: Biomedical Sciences and Euan MacDonald Centre for Motor Neuron Disease Research, Edinburgh, UKDepartment of Neurology and Neurosurgery, UMC Utrecht Brain Center, Utrecht, the NetherlandsDepartment of Neurology and Neurosurgery, UMC Utrecht Brain Center, Utrecht, the NetherlandsDepartment of Neurology and Neurosurgery, UMC Utrecht Brain Center, Utrecht, the NetherlandsDepartment of Neurology and Neurosurgery, UMC Utrecht Brain Center, Utrecht, the NetherlandsEdinburgh Medical School: Biomedical Sciences and Euan MacDonald Centre for Motor Neuron Disease Research, Edinburgh, UKInstitute of Biophysics, CNR Unit, Trento, ItalyDepartment of Neurology and Neurosurgery, UMC Utrecht Brain Center, Utrecht, the NetherlandsDepartment of Neurology and Neurosurgery, UMC Utrecht Brain Center, Utrecht, the NetherlandsDepartment of Neurology and Neurosurgery, UMC Utrecht Brain Center, Utrecht, the Netherlands; Corresponding author: Ewout J.N. Groen, Department of Neurology and Neurosurgery, UMC Utrecht Brain Center, Utrecht, the Netherlands.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 SMN2, 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 SMN2-FL, SMN2Δ7 mRNA, and SMN protein levels were influenced by SMN2 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 SMN2 copy number, and higher SMN levels before treatment predicted better in vitro efficacy. These findings showcase patient-derived fibroblasts as a tool for identifying molecular predictors for personalized treatment.http://www.sciencedirect.com/science/article/pii/S2329050124001955spinal muscular atrophygene therapydisease modelssplice-modifierspersonalized medicine |
| spellingShingle | Ilaria Signoria Maria M. Zwartkruis Lotte Geerlofs Elena Perenthaler Kiterie M.E. Faller Rachel James Harriet McHale-Owen Jared W. Green Joris Kortooms Sophie H. Snellen Fay-Lynn Asselman Thomas H. Gillingwater Gabriella Viero Renske I. Wadman W. Ludo van der Pol Ewout J.N. Groen Patient-specific responses to SMN2 splice-modifying treatments in spinal muscular atrophy fibroblasts Molecular Therapy: Methods & Clinical Development spinal muscular atrophy gene therapy disease models splice-modifiers personalized medicine |
| title | Patient-specific responses to SMN2 splice-modifying treatments in spinal muscular atrophy fibroblasts |
| title_full | Patient-specific responses to SMN2 splice-modifying treatments in spinal muscular atrophy fibroblasts |
| title_fullStr | Patient-specific responses to SMN2 splice-modifying treatments in spinal muscular atrophy fibroblasts |
| title_full_unstemmed | Patient-specific responses to SMN2 splice-modifying treatments in spinal muscular atrophy fibroblasts |
| title_short | Patient-specific responses to SMN2 splice-modifying treatments in spinal muscular atrophy fibroblasts |
| title_sort | patient specific responses to smn2 splice modifying treatments in spinal muscular atrophy fibroblasts |
| topic | spinal muscular atrophy gene therapy disease models splice-modifiers personalized medicine |
| url | http://www.sciencedirect.com/science/article/pii/S2329050124001955 |
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