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CRISPR/Cas9 mediated somatic gene therapy for insertional mutations: the vibrator mouse model
Somatic gene therapy remains technically challenging, especially in the central nervous system (CNS). Efficiency of gene delivery, efficacy in recipient cells, and proportion of cells required for overall benefit are the key points needed to be considered in any therapeutic approach. Recent efforts...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8982555/ https://www.ncbi.nlm.nih.gov/pubmed/35693220 http://dx.doi.org/10.1093/pcmedi/pbab021 |
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author | Fu, Xin Zhu, Jie Duan, Yaou Lu, Paul Zhang, Kang |
author_facet | Fu, Xin Zhu, Jie Duan, Yaou Lu, Paul Zhang, Kang |
author_sort | Fu, Xin |
collection | PubMed |
description | Somatic gene therapy remains technically challenging, especially in the central nervous system (CNS). Efficiency of gene delivery, efficacy in recipient cells, and proportion of cells required for overall benefit are the key points needed to be considered in any therapeutic approach. Recent efforts have demonstrated the efficacy of RNA-guided nucleases such as CRISPR/Cas9 in correcting point mutations or removing dominant mutations. Here we used viral delivered Cas9 plasmid and two guide RNAs to remove a recessive insertional mutation, vibrator (vb), in the mouse brain. The vb mice expressed ∼20% of normal levels of phosphatidylinositol transfer protein, α (PITPα) RNA and protein due to an endogenous retrovirus inserted in intron 4, resulting in early-onset tremor, degeneration of brainstem and spinal cord neurons, and juvenile death. The in situ CRISPR/Cas9 viral treatment effectively delayed neurodegeneration, attenuated tremor, and bypassed juvenile death. Our studies demonstrate the potential of CRISPR/Cas9-mediated gene therapy for insertional mutations in the postnatal brain. |
format | Online Article Text |
id | pubmed-8982555 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-89825552022-06-10 CRISPR/Cas9 mediated somatic gene therapy for insertional mutations: the vibrator mouse model Fu, Xin Zhu, Jie Duan, Yaou Lu, Paul Zhang, Kang Precis Clin Med Research Article Somatic gene therapy remains technically challenging, especially in the central nervous system (CNS). Efficiency of gene delivery, efficacy in recipient cells, and proportion of cells required for overall benefit are the key points needed to be considered in any therapeutic approach. Recent efforts have demonstrated the efficacy of RNA-guided nucleases such as CRISPR/Cas9 in correcting point mutations or removing dominant mutations. Here we used viral delivered Cas9 plasmid and two guide RNAs to remove a recessive insertional mutation, vibrator (vb), in the mouse brain. The vb mice expressed ∼20% of normal levels of phosphatidylinositol transfer protein, α (PITPα) RNA and protein due to an endogenous retrovirus inserted in intron 4, resulting in early-onset tremor, degeneration of brainstem and spinal cord neurons, and juvenile death. The in situ CRISPR/Cas9 viral treatment effectively delayed neurodegeneration, attenuated tremor, and bypassed juvenile death. Our studies demonstrate the potential of CRISPR/Cas9-mediated gene therapy for insertional mutations in the postnatal brain. Oxford University Press 2021-08-19 /pmc/articles/PMC8982555/ /pubmed/35693220 http://dx.doi.org/10.1093/pcmedi/pbab021 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of the West China School of Medicine & West China Hospital of Sichuan University. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Research Article Fu, Xin Zhu, Jie Duan, Yaou Lu, Paul Zhang, Kang CRISPR/Cas9 mediated somatic gene therapy for insertional mutations: the vibrator mouse model |
title | CRISPR/Cas9 mediated somatic gene therapy for insertional mutations: the vibrator mouse model |
title_full | CRISPR/Cas9 mediated somatic gene therapy for insertional mutations: the vibrator mouse model |
title_fullStr | CRISPR/Cas9 mediated somatic gene therapy for insertional mutations: the vibrator mouse model |
title_full_unstemmed | CRISPR/Cas9 mediated somatic gene therapy for insertional mutations: the vibrator mouse model |
title_short | CRISPR/Cas9 mediated somatic gene therapy for insertional mutations: the vibrator mouse model |
title_sort | crispr/cas9 mediated somatic gene therapy for insertional mutations: the vibrator mouse model |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8982555/ https://www.ncbi.nlm.nih.gov/pubmed/35693220 http://dx.doi.org/10.1093/pcmedi/pbab021 |
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