| Title: |
Allele-specific editing ameliorates dominant retinitis pigmentosa in a transgenic mouse model |
| Authors: |
Patrizi, C; Llado, M; Benati, D; Iodice, C; Marrocco, E; Guarascio, R; Surace, EM; Cheetham, ME; Auricchio, A; Recchia, A |
| Source: |
American Journal of Human Genetics , 108 (2) pp. 295-308. (2021) |
| Publication Year: |
2021 |
| Collection: |
University College London: UCL Discovery |
| Subject Terms: |
AAV vector; CRISPR-Cas9 editing; Rhodopsin; retinitis pigmentosa; transgenic mice |
| Description: |
Retinitis pigmentosa (RP) is a group of progressive retinal degenerations of mostly monogenic inheritance, which cause blindness in about 1:3,500 individuals worldwide. Heterozygous variants in the rhodopsin (RHO) gene are the most common cause of autosomal dominant RP (adRP). Among these, missense variants at C-terminal proline 347, such as p.Pro347Ser, cause severe adRP recurrently in European affected individuals. Here, for the first time, we use CRISPR/Cas9 to selectively target the p.Pro347Ser variant while preserving the wild-type RHO allele in vitro and in a mouse model of adRP. Detailed in vitro, genomic, and biochemical characterization of the rhodopsin C-terminal editing demonstrates a safe downregulation of p.Pro347Ser expression leading to partial recovery of photoreceptor function in a transgenic mouse model treated with adeno-associated viral vectors. This study supports the safety and efficacy of CRISPR/Cas9-mediated allele-specific editing and paves the way for a permanent and precise correction of heterozygous variants in dominantly inherited retinal diseases. |
| Document Type: |
article in journal/newspaper |
| File Description: |
text |
| Language: |
English |
| Relation: |
https://discovery.ucl.ac.uk/id/eprint/10121387/ |
| Availability: |
https://discovery.ucl.ac.uk/id/eprint/10121387/1/Cheetham_1-s2.0-S0002929721000069-main.pdf; https://discovery.ucl.ac.uk/id/eprint/10121387/ |
| Rights: |
open |
| Accession Number: |
edsbas.306F1F9 |
| Database: |
BASE |