Treatment Of Retinitis Pigmentosa Research Articles

New Improved cGMP Analogues to Target Rod Photoreceptor Degeneration.

Retinitis pigmentosa (RP) is a form of retinal degeneration affecting a young population with an unmet medical need. Photoreceptor degeneration has been associated with increased guanosine 3',5'-cyclic monophosphate (cGMP), which reaches toxic levels for photoreceptors. Therefore, inhibitory cGMP analogues attract interest for RP treatments. Here we present the synthesis of dithio-CN03, a phosphorodithioate analogue of cGMP, prepared using the H-phosphonothioate route. Two crystal modifications were identified as a trihydrate and a tetrahydrofuran monosolvates. Dithio-CN03 featured a lower aqueous solubility than its RP-phosphorothioate counterpart CN03, a drug candidate, and this characteristic might be favorable for sustained-release formulations aimed at retinal delivery. Dithio-CN03 was tested in vitro for its neuroprotective effects in photoreceptor models of RP. The comparison of dithio-CN03 to CN03 and its diastereomer SP-CN03, and to their phosphate derivative oxo-CN03 identifies dithio-CN03 as the compound with the highest efficacy in neuroprotection and thus as a promising new candidate for the treatment of RP.

Navigating the Usher Syndrome Genetic Landscape: An Evaluation of the Associations between Specific Genes and Quality Categories of Cochlear Implant Outcomes.

Usher syndrome (US) is a clinically and genetically heterogeneous disorder that involves three main features: sensorineural hearing loss, retinitis pigmentosa (RP), and vestibular impairment. With a prevalence of 4-17/100,000, it is the most common cause of deaf-blindness worldwide. Genetic research has provided crucial insights into the complexity of US. Among nine confirmed causative genes, MYO7A and USH2A are major players in US types 1 and 2, respectively, whereas CRLN1 is the sole confirmed gene associated with type 3. Variants in these genes also contribute to isolated forms of hearing loss and RP, indicating intersecting molecular pathways. While hearing loss can be adequately managed with hearing aids or cochlear implants (CIs), approved RP treatment modalities are lacking. Gene replacement and editing, antisense oligonucleotides, and small-molecule drugs hold promise for halting RP progression and restoring vision, enhancing patients' quality of life. Massively parallel sequencing has identified gene variants (e.g., in PCDH15) that influence CI results. Accordingly, preoperative genetic examination appears valuable for predicting CI success. To explore genetic mutations in CI recipients and establish correlations between implant outcomes and involved genes, we comprehensively reviewed the literature to gather data covering a broad spectrum of CI outcomes across all known US-causative genes. Implant outcomes were categorized as excellent or very good, good, poor or fair, and very poor. Our review of 95 cochlear-implant patients with US, along with their CI outcomes, revealed the importance of presurgical genetic testing to elucidate potential challenges and provide tailored counseling to improve auditory outcomes. The multifaceted nature of US demands a comprehensive understanding and innovative interventions. Genetic insights drive therapeutic advancements, offering potential remedies for the retinal component of US. The synergy between genetics and therapeutics holds promise for individuals with US and may enhance their sensory experiences through customized interventions.

IFT27 regulates the long-term maintenance of photoreceptor outer segments in zebrafish

Approximately a quarter of Retinitis Pigmentosa (RP) is caused by mutations in transport-related genes in cilia. IFT27 (Intraflagellar Transport 27), a core component of the ciliary intraflagellar transport (IFT) system, has been implicated as a significant pathogenic gene in RP. The pathogenic mechanisms and subsequent pathology related to IFT27 mutations in RP are largely obscure. Here, we utilized TALEN technology to create an ift27 knockout (ift27-/-) zebrafish model. Electroretinography (ERG) detection showed impaired vision in this model. Histopathological examinations disclosed that ift27 mutations cause progressive degeneration of photoreceptors in zebrafish, and this degeneration was late-onset. Immunofluorescence labeling of outer segments showed that rods degenerated before cones, aligning with the conventional characterization of RP. In cultured human retinal pigment epithelial cells, we found that IFT27 was involved in maintaining ciliary morphology. Furthermore, decreased IFT27 expression resulted in the inhibition of the Hedgehog (Hh) signaling pathway, including decreased expression of key factors in the Hh pathway and abnormal localization of the ciliary mediator Gli2. In summary, we generated an ift27-/- zebrafish line with retinal degeneration which mimicked the symptoms of RP patients, highlighting IFT27′s integral role in the long-term maintenance of cilia via the Hh signaling pathway. This work may furnish new insights into the treatment or delay of RP caused by IFT27 mutations.

The efficacy and safety of transcorneal electrical stimulation for patients with retinitis pigmentosa: a systematic review and meta-analysis

Retinitis pigmentosa (RP) is a heterogeneous group of genetically inherited degenerative disorders characterized by progressive loss of peripheral vision. Tran's corneal electrical stimulation (TES) has been proposed as a treatment for various ocular conditions, but its mechanism remains uncertain. This systematic review and meta-analysis aimed to assess the safety and efficacy of trans-corneal electrical stimulation (TcES) as a treatment for RP by comprehensively examining the available literature in medical databases. The literature of the related studies was retrieved from five databases including central, midline, scopus, directory of open access journals, and clinicalTrials.gov. All of the selected scholarly databases were extensively searched online for articles that were published between January 2019 and July 2023. TES was found to be safe for RP patients, with positive effects on the visual field area (VFA) and scotopic b-wave amplitude. It significantly attenuated the annual decline in the visual field hence effectively doubling its half-life from 10 to 20 years. No significant side effects were observed during TES. TES offers a promising treatment option for RP, with potential benefits in slowing disease progression and preserving vision. The OkuStim system and TES present an affordable and adaptable approach, with opportunities for patient self-administration. However, further studies with larger sample sizes and longer durations are needed to confirm these findings and optimize treatment parameters.

Alterations in glutamate and nitric oxide metabolism in the RdS mice

Aims/Purpose: Nitric oxide (NO) is an essential signalling molecule, with gaseous nature. NO is synthesized by the conversion of L‐arginine to L‐citrulline. This reaction is catalysed by the enzyme nitric oxide synthase (NOS). There are three NOS isoforms, but nNOS reflects most of the production of NO in the retina. Although NO is employed in the retina to maintain ocular function, it has also been related to different visual diseases. Increased levels of NO have been associated with ocular diseases involving increased glutamate concentrations, ischaemia, oxidative stress and inflammation (such as retinitis pigmentosa (RP)). The main purpose of this work was to determine glutamate retinal concentrations at different stages of the retinal degeneration that occurs in the rds mice and to study possible NO metabolism alterations.Methods: Rds mice were treated in accordance with the ARVO statement for the use of animals in ophthalmic and vision research. Mice were sacrificed at different postnatal days (11, 17, 21 and 28). Retinal glutamate concentrations were determined by high pressure liquid chromatography (HPLC). The expression of different enzymes related with NO metabolism (nNOS, guanylate cyclase (GC) and arginase) was determined by histochemistry.Results: Glutamate as well as nNOS was observed to be increased in the retina of rds mice mainly between the peak of rods and cones death. GC was observed to be decreased in the rds mice compared to control ones and no significant changes were observed in arginase expression when we compared rds and control mice.Conclusions: There are alterations in the expression of glutamate, nNOS and GC in rds mice retina compared to control mice. RP is a disease with no effective treatment to date and NO metabolism may be a new target in RP treatment.

The clinical research on the effect of hydrogen-rich water on primary retinitis pigmentosa

ObjectiveTo investigate the feasibility and effectiveness of hydrogen in the treatment of retinitis pigmentosa (RP) patients through the drinking of hydrogen-rich water (HRW). MethodsRP patients clinically diagnosed in our hospital were selected and given HRW for drinking at 400–500 ml twice a day for four consecutive weeks. Changes in best corrected visual acuity (BCVA), intraocular pressure, the retinal thickness, and choroidal thickness, as well as the amplitude and peak time of visual electrophysiological examinations before and after HRW drinking were observed. Data were statistically analyzed. ResultsIn total, 24 eyes of 13 patients with RP (3 males and 10 females aged–27-65 years old, were enrolled in the study. The BCVA after HRW drinking was 0.34 ± 0.25, which was statistically improved compared with that before (P < 0.05). There were no significant differences in intraocular pressure, retinal lhickness, or choroidal thickness before and after HRW drinking (all P > 0.05). The amplitudes of the b-wave in Dark-adaptation 0.01 response, a and b waves in Dark-adaptation 3.0 response, the Dark-adaptation Ops total wave, a and b waves in Light-adaptation 3.0 response, and the Light-adaptation Flicker response of electroretinogram (ERG) were significantly higher than those before HRW drinking (all P < 0.05). The corresponding peak times iwere mproved to some extent compared to those before HRW consumption (all P < 0.05). Six patients with RP (11 eyes) had a BCVAm ore than 20/200. The amplitude and peak time of the P100 -ave from the 1°p attern visual evoked potentials (PVEP) were not significantly different from those before HRW drinking (P > 0.05), while the data from the 15′ PVEP were statistically different (P < 0.05). Seven patients with RP (13 eyes) had a BCVA less than. 20/200 No significant differences were found in the amplitude and peak time of the P2 wave from the 1.0 Hz flash visual evoked potentials (FVEP) and the amplitude from the 12 Hz FVEP compared with those before HRW drinking (all P > 0.05). ConclusionShort-term HRW drinking slightly improved visual function in patients with primary RP, whereas no significant improvement was found in the thickness of the retina and choroid.

AAV-mediated base-editing therapy ameliorates the disease phenotypes in a mouse model of retinitis pigmentosa

Base editing technology is an ideal solution for treating pathogenic single-nucleotide variations (SNVs). No gene editing therapy has yet been approved for eye diseases, such as retinitis pigmentosa (RP). Here, we show, in the rd10 mouse model, which carries an SNV identified as an RP-causing mutation in human patients, that subretinal delivery of an optimized dual adeno-associated virus system containing the adenine base editor corrects the pathogenic SNV in the neuroretina with up to 49% efficiency. Light microscopy showed that a thick and robust outer nuclear layer (photoreceptors) was preserved in the treated area compared with the thin, degenerated outer nuclear layer without treatment. Substantial electroretinogram signals were detected in treated rd10 eyes, whereas control treated eyes showed minimal signals. The water maze experiment showed that the treatment substantially improved vision-guided behavior. Together, we construct and validate a translational therapeutic solution for the treatment of RP in humans. Our findings might accelerate the development of base-editing based gene therapies.

Gene augmentation therapy attenuates retinal degeneration in a knockout mouse model of Fam161a retinitis pigmentosa

Photoreceptor cell degeneration and death is the major hallmark of a wide group of human blinding diseases including age-related macular degeneration and inherited retinal diseases such as retinitis pigmentosa. In recent years, inherited retinal diseases have become the "testing ground" for novel therapeutic modalities, including gene and cell-based therapies. Currently there is no available treatment for retinitis pigmentosa caused by FAM161A biallelic pathogenic variants. In this study, we injected an adeno-associated virus encoding for the longer transcript of mFam161a into the subretinal space of P24-P29 Fam161a knockout mice to characterize the safety and efficacy of gene augmentation therapy. Serial in vivo assessment of retinal function and structure at 3, 6, and 8months of age using the optomotor response test, full-field electroretinography, fundus autofluorescence, and optical coherence tomography imaging as well as ex vivo quantitative histology and immunohistochemical studies revealed a significant structural and functional rescue effect in treated eyes accompanied by expression of the FAM161A protein in photoreceptors. The results of this study may serve as an important step toward future application of gene augmentation therapy in FAM161A-deficient patients by identifying a promising isoform to rescue photoreceptors and their function.

In vivo measurement of mitochondrial ROS production in mouse models of photoreceptor degeneration

Retinitis pigmentosa (RP) is a disease characterised by photoreceptor cell death. It can be initiated by mutations in a number of different genes, primarily affecting rods, which will die first, resulting in loss of night vision. The secondary death of cones then leads to loss of visual acuity and blindness. We set out to investigate whether increased mitochondrial reactive oxygen species (ROS) formation, plays a role in this sequential photoreceptor degeneration. To do this we measured mitochondrial H2O2 production within mouse eyes in vivo using the mass spectrometric probe MitoB. We found higher levels of mitochondrial ROS that preceded photoreceptor loss in four mouse models of RP: Pde6brd1/rd1; Prhp2rds/rds; RPGR−/−; Cln6nclf. In contrast, there was no increase in mitochondrial ROS in loss of function models of vision loss (GNAT−/−, OGC), or where vision loss was not due to photoreceptor death (Cln3). Upregulation of Nrf2 transcriptional activity with dimethylfumarate (DMF) lowered mitochondrial ROS in RPGR−/− mice. These findings have important implications for the mechanism and treatment of RP.

Alleviation of Photoreceptor Degeneration Based on Fullerenols in rd1 Mice by Reversing Mitochondrial Dysfunction via Modulation of Mitochondrial DNA Transcription and Leakage.

Poor therapeutic outcomes of antioxidants in ophthalmologic clinical applications, including glutathione during photoreceptor degeneration in retinitis pigmentosa (RP), are caused by limited anti-oxidative capacity. In this study, fullerenols are synthesized and proven to be highly efficient in vitro radical scavengers. Fullerenol-based intravitreal injections significantly improve the flash electroretinogram and light/dark transition tests performed for 28 days on rd1 mice, reduce the thinning of retinal outer nuclear layers, and preserve the Rhodopsin, Gnat-1, and Arrestin expressions of photoreceptors. RNA-sequencing, RT-qPCR, and Western blotting validate that mitochondrial DNA (mt-DNA)-encoded genes of the electron transport chain (ETC), such as mt-Nd4l, mt-Co1, mt-Cytb, and mt-Atp6, are drastically downregulated in the retinas of rd1 mice, whereas nuclear DNA (n-DNA)-encoded genes, such as Ndufa1 and Atp5g3, are abnormally upregulated. Fullerenols thoroughly reverse the abnormal mt-DNA and n-DNA expression patterns of the ETC and restore mitochondrial function in degenerating photoreceptors. Additionally, fullerenols simultaneously repress Flap endonuclease 1 (FEN1)-mediated mt-DNA cleavage and mt-DNA leakage via voltage-dependent anion channel (VDAC) pores by downregulating the transcription of Fen1 and Vdac1, thereby inactivating the downstream pro-inflammatory cGAS-STING pathway. These findings demonstrate that fullerenols can effectively alleviate photoreceptor degeneration in rd1 mice and serve as a viable treatment for RP.

RECENT THERAPEUTIC ADVANCES &amp; PRECLINICAL PHASES OF RETINITIS PIGMENTOSA

Retinitis pigmentosa (RP) is a group of hereditary illnesses characterized by a slow loss of retinal photoreceptors, which impairs a long-term vision. It is among the most prevalent forms of hereditary retinal dystrophy and has a sizable cost impact on both the individuals affected and the community as a whole. The typical symptoms of this disorder include nyctalopia, loss of the concentric visual field, and finally loss of the bilateral central vision.The primary effect is a progressive loss of vision. One of the main causes of vision loss and blindness in persons under 60, it affects roughly 1.5 million people globally. There is presently no known cure for RP, and the only approved gene therapy, voretigeneneparvovec, is only given to a tiny subset of patients with known RPE65 mutations. Retinoids, vitamin A supplements, sun protection, visual aids, and medical and surgical treatments to treat ocular comorbidities are now the only available therapies, however these merely serve to halt the diseases progression. Given the limited therapeutic landscape, it is vital to develop fresh, personalized therapy modalities that focus on degeneration of the retina. Although the variety of the gene mutations involved makes it difficult to identify a target treatment for RP, new fundamental research indicates an improvement towards comprehending the causes of retinal degeneration. Discovering novel molecular treatments that can specifically target specific receptors or signaling pathways lays the foundation for more effective medication development. The most recent advancements in potential RP treatments are highlighted in this article, with an emphasis on preclinical stage foundational research on molecular targets, which will form the basis for subsequent drug development. We will discuss the alterations that take place to the molecular pathways connected to the growth of RP, with a focus on the ER stress and apoptotic pathways, redox balance maintenance, and genomic stability. Subsequently proceed over the treatment modalities being looked at, like gene and cell therapy, as well as the most recent studies that are discovering new potential drug targets for RP.

Current Management Options for Patients with Retinitis Pigmentosa.

With an estimated prevalence of 1 in 4000 worldwide [1], retinitis pigmentosa (RP) comprises a spectrum of progressive inherited retinal disorders that can lead to blindness as early as age 30 [2]. Despite its relatively high prevalence and devastating consequences, RP does not have a definitive cure. Therapeutic attempts have been made with nutritional supplementation, but these strategies only have proven benefit in a limited number of patients with rare forms of RP. Thus, current standards of care involve regular follow-up, management of associated ocular pathology such as macular edema and cataracts, and genetic counseling and low vision rehabilitation. In recent years, gene therapy, visual prostheses, and stem cell therapy have emerged as FDA-approved treatments for RP, but these options are not yet widely used. Herein, this chapter will discuss the therapeutic strategies listed above that comprise the current standards of care and briefly discuss some emerging options.

Tlr4 gene deletion accelerates retinal degeneration in rd10 and P23H/+ murine models of retinitis pigmentosa

AbstractPurpose: The photoreceptor degeneration associated to retinitis pigmentosa (RP) is caused by a wide variety of genetic mutations, which greatly complicates the development of a universal effective treatment. As a process independent of the causative mutation, the inflammatory response resulting from neuronal death could represent a potential candidate for a general treatment for RP. In this context, we studied the role of TLR4, one of the main mediators of innate immunity, on the retinal degenerative process in two murine models of RP.Methods: rd10 and P23H/+ mice were used to evaluate the consequences of Tlr4 haploinsufficiency and complete deletion on retinal degeneration. Visual function was evaluated by electroretinographic recordings and optomotor test and retinal cytoarchitecture by immunohistology. The myeloid cell population (main mediators of the innate immune response) reactivity was studied by immunohistology and flow cytometry. Gene expression was assessed by RT‐quantitative PCR.Results: We found that Tlr4 expression was significantly increased in the retina of both RP models. To assess the effect of Tlr4 deletion in PR progression first we confirmed that abrogation of Tlr4 expression did not impair visual function in wild‐type animals. However, Tlr4 deficiency accelerated RP progression in both rd10 and P23H/+ mice. Deletion of a single Tlr4 allele reduced the retinal electroretinographic response and photoreceptor survival in both RP models. Moreover, complete abrogation of Tlr4 further exacerbates this phenotype. These results were confirmed by assessing visual acuity by optomotor test in P23H/+ mice. Microglia analysis showed higher proportion of phagocytic microglia and lower of homeostatic microglia in the photoreceptor layers upon Tlr4 total deletion.Conclusions: The TLR4 receptor exerts a neuroprotective effect on the retinal neurodegenerative process in RP, thus suggesting a potential therapeutic target for the disease.

Identification of Small Molecular Chaperones Binding P23H Mutant Opsin through an In Silico Structure-Based Approach.

N-terminal P23H opsin mutation accounts for most of retinitis pigmentosa (RP) cases. P23H functions and folding can be rescued by small chaperone ligands, which contributes to validate mutant opsin as a suitable target for pharmacological treatment of RP. However, the lack of structural details on P23H mutant opsin strongly impairs drug design, and new chemotypes of effective chaperones of P23H opsin are in high demand. Here, a computational-boosted workflow combining homology modeling with molecular dynamics (MD) simulations and virtual screening was used to select putative P23H opsin chaperones among different libraries through a structure-based approach. In vitro studies corroborated the reliability of the structural model generated in this work and identified a number of novel chemotypes of safe and effective chaperones able to promote P23H opsin trafficking to the outer cell membrane.

Neuroinflammation in retinitis pigmentosa: Therapies targeting the innate immune system.

Retinitis pigmentosa (RP) is an important cause of irreversible blindness worldwide and lacks effective treatment strategies. Although mutations are the primary cause of RP, research over the past decades has shown that neuroinflammation is an important cause of RP progression. Due to the abnormal activation of immunity, continuous sterile inflammation results in neuron loss and structural destruction. Therapies targeting inflammation have shown their potential to attenuate photoreceptor degeneration in preclinical models. Regardless of variations in genetic background, inflammatory modulation is emerging as an important role in the treatment of RP. We summarize the evidence for the role of inflammation in RP and mention therapeutic strategies where available, focusing on the modulation of innate immune signals, including TNFα signaling, TLR signaling, NLRP3 inflammasome activation, chemokine signaling and JAK/STAT signaling. In addition, we describe epigenetic regulation, the gut microbiome and herbal agents as prospective treatment strategies for RP in recent advances.

Optical coherence tomography angiography in retinitis pigmentosa: A narrative review.

Retinitis pigmentosa (RP) is a group of inherited retinal disorders characterized by progressive rod and cone photoreceptor degeneration. Changes in retinal vasculature have long been associated with RP. Optical coherence tomography angiography (OCTA) is a novel imaging technology that enables noninvasive visualization of the retinal and choroidal microvasculature. OCTA enables quantification of microvascular changes in the retinal capillary plexus and choriocapillaris, in addition to qualitative feature description. Therefore, OCTA has the potential to become an important tool for better understanding, early detection, progression, and treatment of RP. In this review, we focus on the applications of OCTA in clinical research on RP. We also discuss future improvements in the OCTA technology for RP management. We believe that the advancement of the OCTA technique will ultimately lead to a better understanding of RP and aid in the prevention of visual impairment.

Drinking hydrogen water improves photoreceptor structure and function in retinal degeneration 6 mice

Retinitis pigmentosa (RP) is a genetically heterogeneous group of inherited retinal disorders involving the progressive dysfunction of photoreceptors and the retinal pigment epithelium, for which there is currently no treatment. The rd6 mouse is a natural model of autosomal recessive retinal degeneration. Given the known contributions of oxidative stress caused by reactive oxygen species (ROS) and selective inhibition of potent ROS peroxynitrite and OH·by H2 gas we have previously demonstrated, we hypothesized that ingestion of H2 water may delay the progression of photoreceptor death in rd6 mice. H2 mice showed significantly higher retinal thickness as compared to controls on optical coherence tomography. Histopathological and morphometric analyses revealed higher thickness of the outer nuclear layer for H2 mice than controls, as well as higher counts of opsin red/green-positive cells. RNA sequencing (RNA-seq) analysis of differentially expressed genes in the H2 group versus control group revealed 1996 genes with significantly different expressions. Gene and pathway ontology analysis showed substantial upregulation of genes responsible for phototransduction in H2 mice. Our results show that drinking water high in H2 (1.2–1.6 ppm) had neuroprotective effects and inhibited photoreceptor death in mice, and suggest the potential of H2 for the treatment of RP.

Identification of RPGR ORF15 mutation for X-linked retinitis pigmentosa in a large Chinese family and in vitro correction with prime editor.

X-linked retinitis pigmentosa (XLRP) is the most severe form of Retinitis Pigmentosa (RP) and one of the leading causes of blindness in the world. Currently, there is no effective treatment for RP. In the present study, we recruited a XLRP family and identified a 4 bp deletion mutation (c. 2234_2237del) in RPGR ORF15 with Sanger sequencing, which was located in the exact same region as the missing XES (X chromosome exome sequencing) coverage. Then, we generated cell lines harboring the identified mutation and corrected it via enhanced prime editing system (ePE). Collectively, Sanger sequencing identified a pathogenic mutation in RPGR ORF15 for XLRP which was corrected with ePE. This study provides a valuable insight for genetic counseling of the afflicted family members and prenatal diagnosis, also paves a way for applying prime editing based gene therapy in those patients.

Research Progress in TCM Treatment of Retinitis Pigmentosa

Retinitis pigmentosa (RP) is a genetic eye disease characterized by primary dystrophic degenerative lesions of photoreceptor cells and retinal pigment epithelium. Although there are many treatment methods, there is still a lack of effective methods to restore visual acuity and visual field. Traditional Chinese medicine ophthalmologists have been conducting extensive clinical research on retinitis pigmentosa for a long time and have achieved significant progress. The paper is a summary of the progress of traditional Chinese medicine in the treatment of retinitis pigmentosa in the last five years.

Retinitis pigmentosa 2 pathogenic mutants degrade through BAG6/HUWE1 complex

Retinitis pigmentosa (RP) is the most common inherited retinal degenerative disease which is the major cause of vision loss. X-linked RP patients account for 5%–15% of all inherited RP cases and mutations in RP2 (Retinitis pigmentosa 2) were responsible for about 20% X-linked RP families. A majority of RP2 pathogenic mutations displayed a vulnerable protein stability and degraded rapidly through ubiquitin-proteasome system (UPS). Though the RP2 protein could be readily recovered by proteasome inhibitors, e.g., MG132, their applications for RP2-related RP therapy were limited by their nonspecific characterization. In the present study, we aimed to identify UPS-related factors, such as E3 ligases, which are specifically involved in degradation of RP2 pathogenic mutants. We identified several E3 ligases, such as HUWE1, and the co-chaperon BAG6 specifically interacting with RP2 pathogenic mutants. Knockdown of HUWE1 and BAG6 could partially rescue the reduced protein levels of RP2 mutants. BAG6 is required for recruitment of HUWE1 to ubiquitinate RP2 mutants at the K268 site. The HUWE1 inhibitor BI8622 could restore the levels of RP2 mutant and then the binding to its partner ARL3 in retina cell lines. This study revealed the details of UPS-related degradation of RP2 mutants and possibly provided a potential treatment for RP2-related RP.