Allele-specific editing ameliorates dominant retinitis pigmentosa in a transgenic mouse model
| Autor: | Alberto Auricchio, Enrico Maria Surace, Clarissa Patrizi, Michael E. Cheetham, Daniela Benati, Manel Llado, Alessandra Recchia, Rosellina Guarascio, Carolina Iodice, Elena Marrocco |
|---|---|
| Přispěvatelé: | Patrizi, C., Llado, M., Benati, D., Iodice, C., Marrocco, E., Guarascio, R., Surace, E. M., Cheetham, M. E., Auricchio, A., Recchia, A. |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Transgenic Mice 0302 clinical medicine Genome editing INDEL Mutation CRISPR Missense mutation CRISPR-Cas System Genetics (clinical) Genetics Allele Gene Editing biology CRISPR-Cas9 editing Dependovirus Dependoviru AAV vector Rhodopsin retinitis pigmentosa transgenic mice Alleles Animals CRISPR-Cas Systems Cell Line Disease Models Animal Electroretinography Genetic Therapy Humans Mice Transgenic Mutation Missense Photoreceptor Cells Vertebrate Retina Retinitis Pigmentosa Human Genetically modified mouse Article 03 medical and health sciences Retinitis pigmentosa medicine Photoreceptor Cells Gene Vertebrate Animal medicine.disease eye diseases 030104 developmental biology Mutation Disease Models 030221 ophthalmology & optometry biology.protein Missense |
| Zdroj: | American Journal of Human Genetics |
| Popis: | Summary 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|