Gene Therapy for Rhodopsin-associated Autosomal Dominant Retinitis Pigmentosa.
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ABSTRACT:
SUBMITTER: Massengill MT
PROVIDER: S-EPMC8478325 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Rhodopsin-mediated autosomal dominant retinitis pigmentosa (RHO-adRP) is a hereditary degenerative disorder in which mutations in the gene encoding RHO, the light-sensitive G protein-coupled receptor involved in phototransduction in rods, lead to progressive loss of rods and subsequently cones in the retina. Clinical phenotypes are diverse, ranging from mild night blindness to severe visual impairments. There is currently no cure for RHO-adRP. Although there have been significant advances in gene therapy for inherited retinal diseases, treating RHO-adRP presents a unique challenge since it is an autosomal dominant disease caused by more than 150 gain-of-function mutations in the RHO gene, rendering the established gene supplementation strategy inadequate. This review provides an update on RNA therapeutics and therapeutic editing genome surgery strategies and ongoing clinical trials for RHO-adRP, discussing mechanisms of action, preclinical data, current state of development, as well as risk and benefit considerations. Potential outcome measures useful for future clinical trials are also addressed.
| S-EPMC7545001 | biostudies-literature
Project description:The goal of the study was to identify transcriptional modifications in retinal tissues from mouse model of rhodopsin mutation-associated retinitis pigmentosa (RP), Q344X compared to wild-type (WT). We implemented RNA-sequencing (RNA-seq) at poly(A) selected RNA for transcriptomic profiling. Differentially expressed genes were determined by DESeq2 using the Benjamini & Hochberg p-value adjustment and an absolute log2 fold change cutoff. The results indicate that there is specificity in transcriptional patterns in the retina from Q344x mice relative to WT, including differential expression in the potassium channel gene, Kcnv2, and differential expression in histone genes including the H1 family histone member, H1foo, the H3 histone family 3B, H3f3b, and the histone deacetylase 9, Hdac9.
2018-02-21 | GSE102247 | GEO
Project description:Rhodopsin (RHO) mutations such as Pro23His, are the leading cause of dominantly inherited retinitis pigmentosa in North America. As with other dominant retinal dystrophies, these mutations lead to production of a toxic protein product, and treatment will require knockdown of the mutant allele. The purpose of this study was to develop a CRISPR-Cas9-mediated transcriptional repression strategy using catalytically inactive S. aureus Cas9 (dCas9) fused to the Krüppel-associated box (KRAB) transcriptional repressor domain. Using a reporter construct carrying GFP cloned downstream of the RHO promoter fragment (nucleotides -1403 to +73), we demonstrate a ~74%-84% reduction in RHO promoter activity in RHOpCRISPRi treated vs plasmid only controls. Following subretinal transduction of human retinal explants and transgenic Pro23His mutant pigs, significant knockdown of rhodopsin protein was achieved. Suppression of mutant transgene in vivo was associated with a reduction in ER-stress and apoptosis markers and preservation of photoreceptor cell layer thickness.
2024-03-28 | GSE244786 | GEO
Project description:Mutations in rhodopsin can cause it to misfold and lead to retinal degeneration. A distinguishing feature of these mutants in vitro is that they mislocalize and aggregate. It is unclear whether or not these features contribute to retinal degeneration observed in vivo. The effect of P23H and G188R misfolding mutations were examined in a heterologous expression system and knockin mouse models, including a mouse model generated here expressing the G188R rhodopsin mutant. In vitro characterizations demonstrate that both mutants aggregate, with the G188R mutant exhibiting a more severe aggregation profile compared to the P23H mutant. The potential for rhodopsin mutants to aggregate in vivo was assessed by PROTEOSTAT, a dye that labels aggregated proteins. Both mutants mislocalize in photoreceptor cells and PROTEOSTAT staining was detected surrounding the nuclei of photoreceptor cells. The G188R mutant promotes a more severe retinal degeneration phenotype and greater PROTEOSTAT staining compared to that promoted by the P23H mutant. Here, we show that the level of PROTEOSTAT positive cells mirrors the progression and level of photoreceptor cell death, which suggests a potential role for rhodopsin aggregation in retinal degeneration.
| S-EPMC10873427 | biostudies-literature
Project description:Retinitis pigmentosa (RP) is a genetically highly heterogeneous retinal disease and one of the leading causes of blindness in the world. Next-generation sequencing technology has enormous potential for determining the genetic etiology of RP. We sought to identify the underlying genetic defect in a 35-year-old male from an autosomal-dominant RP family with 14 affected individuals. By capturing next-generation sequencing (CNGS) of 144 genes associated with retinal diseases, we identified eight novel DNA variants; however, none of them cosegregated for all the members of the family. Further analysis of the CNGS data led to identification of a recurrent missense mutation (c.403C > T, p.R135W) in the rhodopsin (RHO) gene, which cosegregated with all affected individuals in the family and was not observed in any of the unaffected family members. The p.R135W mutation has a reference single nucleotide polymorphism (SNP) ID (rs104893775), and it appears to be responsible for the disease in this large family. This study highlights the importance of examining NGS data with reference SNP IDs. Thus, our study is important for data analysis of NGS-based clinical genetic diagnoses.
| S-EPMC4726306 | biostudies-literature
Project description:PurposeEpigenetic and transcriptional mechanisms have been shown to contribute to long-lasting functional changes in adult neurons. The purpose of this study was to identify any such modifications in diseased retinal tissues from a mouse model of rhodopsin mutation-associated autosomal dominant retinitis pigmentosa (ADRP), Q344X, relative to age-matched wild-type (WT) controls.MethodsWe performed RNA sequencing (RNA-seq) at poly(A) selected RNA to profile the transcriptional patterns in 3-week-old ADRP mouse model rhodopsin Q344X compared to WT controls. Differentially expressed genes were determined by DESeq2 using the Benjamini & Hochberg p value adjustment and an absolute log2 fold change cutoff. Quantitative western blots were conducted to evaluate protein expression levels of histone H3 phosphorylated at serine 10 and histone H4. qRT-PCR was performed to validate the expression patterns of differentially expressed genes.ResultsWe observed significant differential expression in 2151 genes in the retina of Q344X mice compared to WT controls, including downregulation in the potassium channel gene, Kcnv2, and differential expression of histone genes, including the H1 family histone member, H1foo; the H3 histone family 3B, H3f3b; and the histone deacetylase 9, Hdac9. Quantitative western blots revealed statistically significant decreased protein expression of both histone H3 phosphorylated at serine 10 and histone H4 in 3-week-old Q344X retinas. Furthermore, qRT-PCR performed on select differentially expressed genes based on our RNA-seq results revealed matched expression patterns of up or downregulation.ConclusionsThese findings provide evidence that transcriptomic alterations occur in the ADRP mouse model rhodopsin Q344X retina and that these processes may contribute to the dysfunction and neurodegeneration seen in this animal model.
| S-EPMC5815338 | biostudies-literature
Project description:Sector and pericentral are two rare, regional forms of retinitis pigmentosa (RP). While usually defined as stable or only very slowly progressing, the available literature to support this claim is limited. Additionally, few studies have analyzed the spectrum of disease within a particular genotype. We identified all cases (9 patients) with an autosomal dominant Rhodopsin variant previously associated with sector RP (RHO c.316G > A, p.Gly106Arg) at our institution. Clinical histories were reviewed, and testing included visual fields, multimodal imaging, and electroretinography. Patients demonstrated a broad phenotypic spectrum that spanned regional phenotypes from sector-like to pericentral RP, as well as generalized disease. We also present evidence of significant intrafamilial variability in regional phenotypes. Finally, we present the longest-reported follow-up for a patient with RHO-associated sector-like RP, showing progression from sectoral to pericentral disease over three decades. In the absence of comorbid macular disease, the long-term prognosis for central visual acuity is good. However, we found that significant progression of RHO p.Gly106Arg disease can occur over protracted periods, with impact on peripheral vision. Longitudinal widefield imaging and periodic ERG reassessment are likely to aid in monitoring disease progression.
| S-EPMC8701931 | biostudies-literature
Project description:Rhodopsin is the G protein-coupled receptor in charge of initiating signal transduction in rod photoreceptor cells upon the arrival of the photon. D190N (Rho(D190n)), a missense mutation in rhodopsin, causes autosomal-dominant retinitis pigmentosa (adRP) in humans. Affected patients present hyperfluorescent retinal rings and progressive rod photoreceptor degeneration. Studies in humans cannot reveal the molecular processes causing the earliest stages of the condition, thus necessitating the creation of an appropriate animal model. A knock-in mouse model with the D190N mutation was engineered to study the pathogenesis of the disease. Electrophysiological and histological findings in the mouse were similar to those observed in human patients, and the hyperfluorescence pattern was analogous to that seen in humans, confirming that the D190N mouse is an accurate model for the study of adRP.
| S-EPMC3388123 | biostudies-literature
Project description:Retinitis pigmentosa is a genetically heterogeneous form of retinal degeneration that affects approximately 1 in 3500 people worldwide. Recently we identified the gene responsible for the RP1 form of autosomal dominant retinitis pigmentosa (adRP) at 8q11-12 and found two different nonsense mutations in three families previously mapped to 8q. The RP1 gene is an unusually large protein, 2156 amino acids in length, but is comprised of four exons only. To determine the frequency and range of mutations in RP1 we screened probands from 56 large adRP families for mutations in the entire gene. After preliminary results indicated that mutations seem to cluster in a 442 nucleotide segment of exon 4, an additional 194 probands with adRP and 409 probands with other degenerative retinal diseases were tested for mutations in this region alone. We identified eight different disease-causing mutations in 17 of the 250 adRP probands tested. All of these mutations are either nonsense or frameshift mutations and lead to a severely truncated protein. Two of the eight different mutations, Arg677X and a 5 bp deletion of nucleotides 2280-2284, were reported previously, while the remaining six mutations are novel. We also identified two rare missense changes in two other families, one new polymorphic amino acid substitution, one silent substitution and a rare variant in the 5'-untranslated region that is not associated with disease. Based on this study, mutations in RP1 appear to cause at least 7% (17/250) of adRP. The 5 bp deletion of nucleotides 2280-2284 and the Arg677X nonsense mutation account for 59% (10/17) of these mutations. Further studies will determine whether missense changes in the RP1 gene are associated with disease, whether mutations in other regions of RP1 can cause forms of retinal disease other than adRP and whether the background variation in either the mutated or wild-type RP1 allele plays a role in the disease phenotype.
| S-EPMC2585827 | biostudies-literature
Project description: Not available
| S-EPMC9992370 | biostudies-literature