Removal of a partial genomic duplication restores synaptic transmission and behavior in the MyosinVA mutant mouse Flailer
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Fecha
2023-12
Profesor/a Guía
Facultad/escuela
Idioma
en
Título de la revista
ISSN de la revista
Título del volumen
Editor
BioMed Central Ltd
Nombre de Curso
Licencia CC
CC BY 4.0 DEED Attribution 4.0 International
Licencia CC
https://creativecommons.org/licenses/by/4.0/
Resumen
Background: 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. Results: Using the ASD and anxiety mouse model Flailer, which contains a partial genomic duplication working as a dominant negative for MyoVa, we demonstrate the use of DN-CRISPRs to remove a 700 bp genomic region in vitro and in vivo. Importantly, DN-CRISPRs have not been used to remove genomic regions using sgRNA with an offset greater than 300 bp. 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 editing. Delivery of DN-CRISPRs in vivo shows that local delivery to the ventral hippocampus can rescue some of the mutant behaviors, while intracerebroventricular delivery, completely recovers the Flailer animal phenotype associated to anxiety and ASD. Conclusions: Our results demonstrate the potential of DN-CRISPR to efficiently remove larger genomic duplications, working as a new gene therapy approach for treating neurodegenerative diseases. © 2023, BioMed Central Ltd., part of Springer Nature.
Notas
Indexación: Scopus.
Palabras clave
Anxiety, ASD, DN-CRISPR, Gene-editing, Therapy
Citación
BMC Biology. Volume 21, Issue 1. December 2023. Article number 232
DOI
10.1186/s12915-023-01714-y