Removal of a genomic duplication by double-nicking CRISPR restores synaptic transmission and behavior in the MyosinVA mutant mouse Flailer.
| العنوان: | Removal of a genomic duplication by double-nicking CRISPR restores synaptic transmission and behavior in the MyosinVA mutant mouse Flailer. |
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| المؤلفون: | Bustos FJ, Pandian S, Haensgen H, Zhao JP, Strouf H, Heidenreich M, Swiech L, Deverman B, Gradinaru V, Zhang F, Constantine-Paton M |
| المصدر: | BioRxiv : the preprint server for biology [bioRxiv] 2023 Apr 28. Date of Electronic Publication: 2023 Apr 28. |
| نوع المنشور: | Preprint |
| اللغة: | English |
| بيانات الدورية: | Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| مستخلص: | Copy number variations, and particularly duplications of genomic regions, have been strongly associated with various neurodegenerative conditions including autism spectrum disorder (ASD). These genetic variations have been found to have a significant impact on brain development and function, which can lead to the emergence of neurological and behavioral symptoms. Developing strategies to target these genomic duplications has been challenging, as the presence of endogenous copies of the duplicate genes often complicates the editing strategies. Using the ASD and anxiety mouse model Flailer, that contains a duplication working as a dominant negative for MyoVa, we demonstrate the use of DN-CRISPRs to remove a 700bp genomic duplication in vitro and in vivo . Importantly, DN-CRISPRs have not been used to remove more gene regions <100bp successfully and with high efficiency. We found that editing the flailer gene in primary cortical neurons reverts synaptic transport and transmission defects. Moreover, long-term depression (LTD), disrupted in Flailer animals, is recovered after gene edition. Delivery of DN-CRISPRs in vivo shows that local delivery to the ventral hippocampus can rescues some of the mutant behaviors, while intracerebroventricular delivery, completely recovers Flailer animal phenotype associated to anxiety and ASD. Our results demonstrate the potential of DN-CRISPR to efficiently (>60% editing in vivo) remove large genomic duplications, working as a new gene therapy approach for treating neurodegenerative diseases. |
| التعليقات: | Update in: BMC Biol. 2023 Nov 14;21(1):232. (PMID: 37957716) |
| تواريخ الأحداث: | Date Created: 20230510 Latest Revision: 20240108 |
| رمز التحديث: | 20240109 |
| مُعرف محوري في PubMed: | PMC10168395 |
| DOI: | 10.1101/2023.04.28.538685 |
| PMID: | 37163068 |
| قاعدة البيانات: | MEDLINE |
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