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.

Allele-specific editing ameliorates dominant retinitis pigmentosa in a transgenic mouse model / Patrizi, C.; Llado, M.; Benati, D.; Iodice, C.; Marrocco, E.; Guarascio, R.; Surace, E. M.; Cheetham, M. E.; Auricchio, A.; Recchia, A.. - In: AMERICAN JOURNAL OF HUMAN GENETICS. - ISSN 0002-9297. - 108:2(2021), pp. 295-308. [10.1016/j.ajhg.2021.01.006]

Allele-specific editing ameliorates dominant retinitis pigmentosa in a transgenic mouse model

Patrizi C.;Benati D.;Recchia A.
2021

Abstract

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.
2021
108
2
295
308
Allele-specific editing ameliorates dominant retinitis pigmentosa in a transgenic mouse model / Patrizi, C.; Llado, M.; Benati, D.; Iodice, C.; Marrocco, E.; Guarascio, R.; Surace, E. M.; Cheetham, M. E.; Auricchio, A.; Recchia, A.. - In: AMERICAN JOURNAL OF HUMAN GENETICS. - ISSN 0002-9297. - 108:2(2021), pp. 295-308. [10.1016/j.ajhg.2021.01.006]
Patrizi, C.; Llado, M.; Benati, D.; Iodice, C.; Marrocco, E.; Guarascio, R.; Surace, E. M.; Cheetham, M. E.; Auricchio, A.; Recchia, A.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1236862
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