Gene augmentation for autosomal dominant retinitis pigmentosa using rhodopsin genomic loci nanoparticles in the P23H +/- knock-in murine model

Gene therapy for autosomal dominant retinitis pigmentosa (adRP) is challenged by the dominant inheritance of the mutant genes, which would seemingly require a combination of mutant suppression and wild-type replacement of the appropriate gene. We explore the possibility that delivery of a nanopartic...

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Bibliographic Details
Published in:Gene therapy 2023-08, Vol.30 (7-8), p.628-640
Main Authors: Sp, Simna, Mitra, Rajendra N, Zheng, Min, Chrispell, Jared D, Wang, Kai, Kwon, Yong-Su, Weiss, Ellen R, Han, Zongchao
Format: Article
Language:English
Subjects:
Animal models
Enhancers
Gene loci
Gene therapy
Genomics
MicroRNAs
miRNA
Mutants
Nanoparticles
Next-generation sequencing
Photoreceptors
Recovery of function
Regulatory sequences
Retinal degeneration
Retinitis
Retinitis pigmentosa
Rhodopsin
Structure-function relationships
Transcriptomes
Transgenes
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Summary:Gene therapy for autosomal dominant retinitis pigmentosa (adRP) is challenged by the dominant inheritance of the mutant genes, which would seemingly require a combination of mutant suppression and wild-type replacement of the appropriate gene. We explore the possibility that delivery of a nanoparticle (NP)-mediated full-length mouse genomic rhodopsin (gRho) or human genomic rhodopsin (gRHO) locus can overcome the dominant negative effects of the mutant rhodopsin in the clinically relevant P23H -knock-in heterozygous mouse model. Our results demonstrate that mice in both gRho and gRHO NP-treated groups exhibit significant structural and functional recovery of the rod photoreceptors, which lasted for 3 months post-injection, indicating a promising reduction in photoreceptor degeneration. We performed miRNA transcriptome analysis using next generation sequencing and detected differentially expressed miRNAs as a first step towards identifying miRNAs that could potentially be used as rhodopsin gene expression enhancers or suppressors for sustained photoreceptor rescue. Our results indicate that delivering an intact genomic locus as a transgene has a greater chance of success compared to the use of the cDNA for treatment of this model of adRP, emphasizing the importance of gene augmentation using a gDNA that includes regulatory elements.
ISSN:0969-7128
1476-5462
DOI:10.1038/s41434-023-00394-1