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.
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The raw sequencing reads of all libraries (GSE153053) are publicly available online at the Gene Expression Omnibus (GEO). Datasets can be downloaded.
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The authors thank Dr. Hemant Kelkar (Department of Genetics) for his critical comments and scientific guidance. This work was supported by the U.S. National Eye Institute (R01EY026564, ZH; R01EY012224, ERW), and in part by Pfizer-NC Biotech Gene Therapy Fellowship Program for Dr. Kai Wang (NCBC Grant #2020-GTF-6902, ZH); the Bright Focus Foundation (M2019063, ZH), and the Edward N. & Della L. Thome Memorial Foundation (138289, ZH).
The authors declare no competing interests.
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SP, S., Mitra, R.N., Zheng, M. et al. Gene augmentation for autosomal dominant retinitis pigmentosa using rhodopsin genomic loci nanoparticles in the P23H+/− knock-in murine model. Gene Ther (2023). https://doi.org/10.1038/s41434-023-00394-1