Retinitis Pigmentosa Research Articles

DCasMINI-mediated therapy rescues photoreceptors degeneration in a mouse model of retinitis pigmentosa.

Retinitis pigmentosa (RP) is characterized by degeneration of rod and cone photoreceptors that progresses to irreversible blindness. Now, there are no mutation-agnostic approaches to treat RP. Here, we utilized a single adeno-associated virus (AAV)-based CRISPR activation system to activate phosphodiesterase 6B (Pde6b) to mitigate the severe degeneration in Pde6anmf363 mice. We demonstrate that transcriptional activation of Pde6b can rescue the loss of Pde6a, with preservation of retinal structure, restoration of electroretinography responses, and improvement of visual function as assessed by optokinetic response and looming-induced escape behaviors. These findings demonstrate the therapeutic potential of a dCasMINI-mediated activation strategy that provides a mutation-independent treatment for retinal degeneration. This study offers a promising therapeutic approach for RP and potentially other forms of genetic diseases.

CD3+CD4-CD8- Double-Negative Lymphocytes Are Increased in the Aqueous Humor of Patients with Retinitis Pigmentosa: Their Possible Role in Mediating Inflammation

Recently, evidence has supported a significant role for immune and oxidative-mediated damage underlying the pathogenesis of different types of retinal diseases, including retinitis pigmentosa (RP). Our study aimed to evaluate the presence of immune cells and mediators in patients with RP using flow cytometric analysis of peripheral blood (PB) and aqueous humor (AH) samples. We recruited 12 patients with RP and nine controls undergoing cataract surgery. Flow cytometric analysis of PB and AH samples provided a membrane staining that targeted surface molecules (CD14, CD16, CD19, CD3, CD4, CD8, and CD161) identifying monocytes, natural killer (NK) cells, B cells, T cells, and T subpopulations, respectively. Moreover, lymphocytes were polyclonally stimulated to evaluate cytokine (CK) production at single-cell level. The circulating immune cell distribution was comparable between patients with RP and controls. Conversely, in the AH of controls we could detect no cells, while in the RP AH samples we found infiltrating leukocytes, consisting of T (CD3+), B (CD19+), NK (CD16+CD3-) cells, and monocytes (CD14+). In patients with RP, the frequency of most infiltrating immune cell populations was similar between the AH and PB. However, among T cell subpopulations, the frequency of CD3+CD4+ T cells was significantly lower in the RP AH compared to RP PB, whereas CD3+CD4-CD8- double-negative (DN) T cells were significantly higher in the RP AH compared to RP PB. Cytokine production analysis revealed a trend toward an increased frequency of CD3+CD8-CD161+IFN-ɣ-producing cells and a decreased frequency of CD3+CD8+IL-4-producing cells in the RP AH compared to RP PB. The detection of immune cells, particularly DN T cells, and a Th1-skewed phenotype in RP AH suggests immune-mediated and inflammatory mechanisms in the disease.

Macular retinal nerve fiber layer thickness in retinitis pigmentosa patients with and without optic disc drusen

IntroductionRetinitis pigmentosa (RP) is a group of inherited retinal dystrophies characterized by progressive photoreceptor degeneration. In a recent study, we reported co-existing optic disc drusen (ODD) at 30%, a prevalence 15 times higher than in the general population. The aims of this study were to a) assess if macular retinal nerve fiber layer thickness (RNFLt) was increased in our cohort of RP patients and b) compare RNFLt between RP patients with and without ODD.MethodsIn this post-hoc analysis, optical coherence tomography (OCT) scans of patients with RP and healthy controls were manually delineated, and macular RNFLt measurements were obtained. The analyses were conducted both a) for RP patients without ODD compared to controls and b) for RP patients with and without ODD.ResultsOCT scans of 32 patients with RP and 13 healthy controls were included. Macular RNFLt was significantly increased in RP patients compared to healthy controls and in RP patients with ODD compared to RP patients without ODD.DiscussionFurther studies will explore whether increased RNFLt leads to ODD development through dystrophic calcification or, conversely, if ODD in combination with RP-associated retinal ganglion cell damage causes the increased RNFLt through retrograde axoplasmic stasis.

Efficacy and safety of minocycline in retinitis pigmentosa: a prospective, open-label, single-arm trial

Retinitis pigmentosa (RP) is characterized by progressive photoreceptor cells death accelerated by the proliferation and activation of microglia pathologically. No consensus exists on the treatment. Minocycline is recognized as a microglia inhibitor with great anti-inflammatory and neuro-protective functions. However, efficacy of minocycline in RP patients is lacking. We conducted a prospective, open-label, and single-arm trial, in which daily oral minocycline of 100 mg was administered for 12 months in RP patients with light-adapted 30 Hz flicker electroretinography (ERG) amplitude >0 µV in at least one eye (NCT04068207). The primary outcome was the proportion of participants with improvement in the ERG amplitude at month 12. The secondary outcomes included improvements of the following items: other ERGs amplitudes, visual field, best-corrected visual acuity, contrast sensitivity, color vision, and NEI-VFQ-25. 35 of 288 patients met inclusive criteria were enrolled (median [IQR] age, 36 [31–45] years; 17 female [48.6%]). 32 participants completed all examinations, while 3 participants completed the 12-month online visit via conducting NEI-VFQ-25. The primary outcome showed improvement was 34.3% (12 of 35 [95% CI 19.1–52.2]). Similarly, all secondary outcomes showed improvements. Adverse events were reported in 22 participants (62.9%) and were all resolved without extra medication during the study period. No severe adverse events were recorded. Our findings identified daily oral minocycline of 100 mg for 12 months was beneficial in improving the visual function of RP patients with good safety. This study indicates minocycline may be a promising therapy for RP, but a randomized controlled trial is still needed of further exploration.

The Future of Nanomaterials Tackling the Challenge of Delivering Nucleic Acids to the Retina

AbstractOcular gene therapy targets eye diseases at the genetic level. Systemic transport of nucleic acids to ocular tissues poses a significant challenge, as the effectiveness of crossing the blood‐retina barrier limits nucleic acid penetration. Therefore, local administration, such as topical, periocular, or intraocular, can improve the outcome of in vivo gene therapy by bypassing the first‐pass effect and minimizing the systemic toxic effects. The eye is an immune‐privileged organ with limited local immune response, making it an ideal candidate for local gene therapy. Ocular gene therapy offers a promising solution for the treatment of a wide range of retinal diseases including age‐related macular degeneration, diabetic retinopathy, retinitis pigmentosa, and Leber congenital amaurosis. Gene therapy enables replacement of mutated genes essential for visual function, delivery of genes expressing neurotrophic factors and anti‐apoptosis factors for retinal degeneration, and delivery of genes expressing anti‐angiogenic proteins for ocular neovascularization. This perspective discusses the potential of nanoparticles for nucleic acid delivery to the retina, explores challenges, and evaluates different delivery methods, including non‐viral agents such as liposomes and polymers. These nonviral agents present advantages over traditional viral vectors, showing promise in overcoming limitations and offering a viable option for retinal gene therapy.

Efficient Assessment of Progression in Clinical Trials in Retinitis Pigmentosa.

To conduct a simulation study to evaluate the effect of disease stage, frequency, and clustering of visual field (VF) tests, and inclusion of one or both eyes on sample size calculation in clinical trials on retinitis pigmentosa. A series of VFs were simulated on the basis of test-retest VF data in the early, moderate, and advanced stages of retinitis pigmentosa. VF measurements were scheduled 8 times in approximately 2 years. The probability to detect significant difference between treatment and control groups was measured. The investigation was conducted for 50%, 40%, 30%, 20% and 10% treatment effects. When only one eye was used in each patient with a treatment effect of 50%, 80% probability of significance was observed in the moderate stage when sample size was 70 eyes in each arm (140 eyes in both arms). Early stage disease and inclusion of both eyes decreased this number to 30 eyes (60 eyes in both arms); these decreasing effects were larger than performing additional VFs at the beginning and end of the observation. A similar tendency was observed with 40%, 30%, 20% and 10% treatment effects. When planning a clinical trial, it is important to consider disease stage, in addition to VF schedule and inclusion of one or both eyes.

Assessing Contrast Sensitivity Function in CRB1-Retinopathies: Exploring Child-Friendly Measures of Visual Function.

Mutations affecting the CRB1 gene can result in a range of retinal phenotypes, including early onset severe retinal dystrophy/Leber congenital amaurosis (EOSRD/LCA), retinitis pigmentosa, cone-rod dystrophy (CORD), and macular dystrophy (MD). As research into treatment strategies advances towards clinical translation, there is a need to establish reliable outcome metrics. This study explores the contrast sensitivity function (CSF) across different spatial frequencies in individuals with CRB1-retinopathies using the child-friendly PopCSF test, an iPad-based "gamified" assessment. Prospective cross-sectional study of 20 patients with molecularly confirmed biallelic CRB1 pathogenic variants from Moorfields Eye Hospital, London, UK, was conducted. Best-corrected visual acuity (BCVA), contrast sensitivity using the Pelli-Robson chart, and the PopCSF test were performed. Of the 20 CRB1 patients, seven had EOSRD/LCA, three had CORD, and 10 had MD. There was no statistically significant difference between the mean BCVA between phenotypes (P = 0.066). However, a significant difference was found between groups in the mean letter log contrast sensitivity (logCS) and area under the contrast sensitivity function (AUCSF) with P = 0.047 and P < 0.001, respectively. A moderate positive correlation was observed between Pelli-Robson and PopCSF (r = 0.53, P = 0.020). The CRB1 cohort had significantly lower CSF at both low and high spatial frequencies compared to controls. Among the CRB1 phenotypes, patients with EOSRD/LCA, exhibited the lowest CSF. This study is the first to examine CSF across spatial frequencies in patients with CRB1-retinopathies using the novel PopCSF test. The CSF holds promise as a potential functional vision trial endpoint.

Generation of the human iPSC line ESi132-A from a patient with retinitis pigmentosa caused by a mutation in the PRPF31 gene

Generation of the human iPSC line ESi132-A from a patient with retinitis pigmentosa caused by a mutation in the PRPF31 gene

Subretinal Gene Therapy Drug AGTC-501 for XLRP Phase 1/2 Multicenter Study (HORIZON): 24-Month Safety and Efficacy Results: Subretinal Gene Therapy AGTC-501 for XLRP Ph 1/2 24M Results

PurposeTo evaluate the safety and efficacy of subretinal gene therapy using AGTC-501 (rAAV2tYF-GRK1-RPGR) in male participants with X-linked retinitis pigmentosa (XLRP). DesignPhase 1/2, open-label, dose-escalation study. MethodsSetting: Four centers in the United States. Patient or Study Population: Twenty-nine males with XLRP and confirmed pathogenic RPGR variants. Mean age was 31.6 years (range 15-55). Intervention: Subretinal injection of AGTC-501 at doses ranging from 2.48 × 1010 to 1.99 × 1012 vg/eye administered in one eye per participant. Subretinal injection sites initially targeted the peripheral retina and then transitioned to the macula with successive cohorts. Main Outcome Measures: Treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), laboratory parameters, and immunological responses. Efficacy was evaluated by mesopic microperimetry mean sensitivity. ResultsAll 29 participants experienced ≥1 TEAE. Eleven (38%) experienced ≥1 grade 3 TEAE. Six (21%) experienced ≥1 ocular SAE related to AGTC-501, including retinal detachment (n=4), subcapsular cataract (n=1), and glaucoma (n=1). Two (6.9%) experienced non-ocular treatment-emergent SAEs. Immunological findings did not indicate safety concerns. Three of 4 participants at the highest dose exhibited concerning retinal pigment epithelial changes. Half the participants at the highest tolerated dose (6.8 × 1011vg/eye) maintained ≥7 dB improvement in ≥5 loci at 24 months. ConclusionsSubretinal AGTC-501 was generally well-tolerated. Despite all participants experiencing at least one TEAE, most of these events were mild in nature, exhibited complete resolution, and were associated with the subretinal injection procedure itself rather than the study agent. The highest dose exhibited an unfavorable risk-benefit profile due to the development of RPE changes. Although this group had the highest improvement in retinal sensitivity, our team has decided not to continue this dose in future clinical trials. Preliminary efficacy was observed at the maximum tolerated dose. Further studies are warranted to assess long-term safety and efficacy of AGTC-501 for XLRP treatment.

Pediatric Usher Syndrome Type 2A with Coexisting Rheumatic Heart Disease and Upper Gastro-Intestinal Bleed: A Case Report

Usher syndrome is a rare autosomal recessive disorder characterized by progressive sensorineural hearing loss and retinitis pigmentosa, typically present from birth and later symptoms, including loss of night vision and peripheral vision slowly progressing to blindness. The condition exhibits clinical and genetic diversity and currently lacks the definitive treatment. This report presents a case of a ten-year-old female diagnosed with Usher syndrome type IIA via whole exome sequencing. The delayed onset of visual symptoms often leads to a misdiagnosis to isolated deafness in early years. The early identification allows for better prognosis through surveillance and intervention in hearing and visual impairments. If usher patients can receive a timely diagnosis, genetic molecular therapies may help preserve the photoreceptors, subsequently development of blindness could be delayed or possibly be prevented.

Two Cases of Peripheral Pigmentary Retinopathy in a Korean Family with Danon Disease : Case Report

Two Cases of Peripheral Pigmentary Retinopathy in a Korean Family with Danon Disease : Case Report

The phenotypic spectrum of CEP250 gene variants

ABSTRACT Introduction Classically, Usher syndrome is characterized by the association of sensorineural hearing loss (SNHL), retinitis pigmentosa (RP) and possible vestibular dysfunction. Pathogenic bi-allelic variants in CEP250 cause atypical autosomal recessive Usher syndrome, which is associated with SNHL and photoreceptors 20 dysfunction without vestibular signs. To date, only 19 scattered descriptions have been reported. In this study, we present detailed clinical and genetic description of 7 unrelated individuals with CEP250 related disease, along with a literature review to provide new insight on the severity and course of the disease. Methods We retrospectively recruited 7 unrelated individuals who underwent genetic testing (targeted gene panel or whole genome sequencing) and were found to carry CEP250 pathogenic variants. Results Most patients (5/7) 25 exhibit both retinal dystrophy and SNHL. Two patients appear to present either isolated hearing loss or visual impairment, but further investigations are needed to confirm a possible non-syndromic presentation. All patients harbored isolated truncating variants. Discussion CEP250 pathogenic variants are associated with post-lingual SNHL, and most often progressive photoreceptor dysfunction. The disease may begin with ocular features or hearing loss. We strongly recommend genetic analysis of classical and atypical Usher 30 related-genes, in patients with isolated retinal dystrophy or SNHL. We also recommend ophthalmological evaluation and follow-up in patients with isolated SNHL, and conversely. The coexistence of loss- and gain-of-function effects may exist, complicating the development of gene therapy.

Retinal pigment epithelial cells reduce vascular leak and proliferation in retinal neovessels

In multiple neurodegenerative diseases, including age-related macular degeneration, retinitis pigmentosa, and macular telangiectasia type 2 (MacTel), retinal pigment epithelial (RPE)-cells proliferate and migrate into the neuroretina, forming intraretinal pigment plaques. Though these pigmentary changes are hallmarks of disease progression, it is unknown if their presence is protective or detrimental.Here, we first evaluated the impact of pigment plaques on vascular changes and disease progression in MacTel. In a retrospective, longitudinal study, we analyzed multimodal retinal images of patients with MacTel and showed that pigment plaques were associated with decreased vascular leakage and stabilized neovascular growth. We then modeled the underlying pathomechanisms of pigment plaque formation in aberrant neovascular growth using the very-low-density lipoprotein receptor mutant (Vldlr−/−) mouse. Our data indicated that during RPE-proliferation, migration and accumulation along neovessels RPE-cells underwent epithelial-mesenchymal transition (EMT). Pharmacologic inhibition of EMT in Vldlr−/− mice decreased pigment coverage, and exacerbated neovascular growth and vascular leakage.Our findings indicate that the proliferation, migration and perivascular accumulation of RPE-cells stabilize vascular proliferation and exudation, thereby exerting a protective effect on the diseased retina. We conclude that interfering with this “natural repair mechanism” may have detrimental effects on the course of the disease and should thus be avoided.

Clinical Characteristics and Treatment Outcomes in Unilateral Coats disease – a Global Collaborative Study

To evaluate the clinical outcomes and prognostic factors in unilateral Coats disease in the era of anti-VEGF therapy. Global, multicenter, retrospective case series. 656 eyes of 656 subjects with Coats disease were included in this study. Exclusion criteria were Coats disease secondary to retinitis pigmentosa as well as bilateral cases. Clinical data from patients with Coats disease were collected from 20 ophthalmic practices around the world. We compared early-stage (stage 1-2) and advanced-stage (stage 3-5) Coats disease in terms of clinical characteristics and treatment modalities. Functional outcomes include achieving visual acuity (VA) of 0.3 logMAR or better and VA improvement or stability. Anatomical failure was defined as the development of phthisis, chronic retinal detachment, massive fibrosis, or the requirement for enucleation. Subjects with early-stage disease were significantly older, with a mean age of 17.4 ± 17.8 years, compared to 7.1 ± 7.1 years in the advanced-stage group (p < 0.001). There was a male predominance in both early and advanced stages (84.7%). Advanced disease was associated with a higher incidence of strabismus (20.2% vs. 6.7%, p < 0.001) and leukocoria (12.3% vs. 3.2%, p < 0.001). More subjects with early-stage disease received laser photocoagulation as monotherapy (44.7% vs. 21.1%, p < 0.001). Additionally, early-stage disease received more sessions of intravitreal anti-VEGF injections as adjunct therapy (4.4 ± 6.2 vs. 2.7 ± 2.1, p = 0.005). Factors associated with poorer functional outcomes included worse presenting visual acuity, advanced disease stage, and the presence of a foveal nodule. Worse presenting visual acuity and advanced disease stage was associated with lower likelihood of anatomical success while combination therapy increased the odds of anatomical success. Unilateral Coats disease predominantly affects males, regardless of disease stage. Identifying a foveal nodule is crucial for visual prognosis. Laser photocoagulation remains the primary treatment. While anti-VEGF may prevent enucleation, its role in early-stage disease requires further clarification.

Single-Cell Transcriptomic Dataset of RPGR-associated Retinitis Pigmentosa Patient-Derived Retinal Organoids

X-linked retinitis pigmentosa (XLRP) is a severe hereditary retinal disorder marked by progressive vision loss due to photoreceptor dysfunction. The retinitis pigmentosa GTPase regulator (RPGR) gene, responsible for most XLRP cases, encodes a protein crucial for the transport of visual signal proteins between the photoreceptor inner and outer segments. However, the mechanism of RPGR mutation causing photoreceptor disorder is not clear and effective treatments remain elusive. This study utilized retinal organoids (ROs) derived from normal and RPGR-mutant human induced pluripotent stem cells (hiPSC) at four developmental stages (40, 90, 150, and 200 days). Single-cell RNA sequencing (scRNA-seq) was conducted on 71,096 cells, including 33,839 cells from the control group and 37,257 cells from the RPGR group. Key retinal cell types were identified and the obtained scRNAseq dataset was validated reliable and high -quality. This study has provided data resources and references for exploring the mechanism of RPGR-related retinal degeneration and support the development of targeted therapies.

Test-retest variability of mesopic microperimetry-associated parameters in patients with retinitis pigmentosa: REPEAT Study Report No. 2.

Understanding test-retest variability (TRV) of mesopic microperimetry is critical for defining meaningful treatment effects in retinitis pigmentosa (RP) trials. This study uniquely evaluates intra- and intervisit TRV and coefficients of repeatability (CoRs) for microperimetry parameters in RP patients with varying best-corrected visual acuity (BCVA) levels. In this single-centre prospective cohort study, RP patients were assessed on two visits, 14.0 days apart. Patients were grouped by BCVA: low (≤20/50 Snellen; ≥0.4 logMAR) or moderate (>20/50 Snellen; <0.4 logMAR). Using Bland-Altman analyses, the CoRs for intra- and intervisit variability were determined for pointwise (dB), mean (dB), and volume sensitivity (dB*deg2) on mesopic microperimetry. Intravisit CoRs for mean, volume, and pointwise sensitivity were 1.7 dB, 353.2 dB*deg2, and 8.6 dB, respectively, in the low-BCVA group (n = 32), and 0.9 dB, 254.5 dB*deg2, and 7.3 dB in the moderate-BCVA group (n = 15). Intervisit CoRs for mean, volume, and pointwise sensitivity were 2.4 dB, 355.2 dB*deg2, and 10.2 dB in the low-BCVA group (n = 31). The moderate-BCVA group (n = 16) showed smaller CoRs of 1.6 dB, 386.8 dB*deg2, and 7.7 dB for mean, volume, and pointwise sensitivity. BCVA and mean sensitivity, but not fixation stability, are predictors of TRV for volume sensitivity. Due to significant TRV, pointwise sensitivity is an unreliable endpoint for RP patients, irrespective of BCVA. Mean sensitivity is suitable as an endpoint when BCVA is relatively preserved. Volume sensitivity provides additional spatial information, and shows promise as a clinical endpoint for assessing macular sensitivity changes on mesopic microperimetry in patients with RP.

Self-reported visual function and in-depth swept-source optical coherence tomography features of cystoid macular edema in retinitis pigmentosa

PurposeTo evaluate self-reported visual function in retinitis pigmentosa (RP) patients with and without cystoid macular edema (CME) and to explore associations between cystoid spaces (CS), retinal morphometric parameters, and clinical data using swept-source optical coherence tomography (SS-OCT).MethodsIn this cross-sectional case-control study (1:3) conducted at an Inherited Retinal Degenerations referral center in Portugal, RP patients with and without CME (matched for age and gender) completed the Michigan Retinal Degeneration Questionnaire (MRDQ) and underwent SS-OCT. Morphometric analysis, including ellipsoid zone area (EZA), was performed by two independent graders. In the CME group, detailed CS analysis was conducted. Correlations between clinical data - age, gender, best-corrected visual acuity (BCVA) - and MRDQ domains were evaluated.ResultsThe study included 23 RP patients with CME (60.87% male, mean age 44.65 ± 13.58 years) and 69 without CME (49.28% male, mean age 47.94 ± 14.39 years). No significant differences were found between groups in almost all MRDQ domains, BCVA, or EZA. Age positively correlated with 4 MRDQ domains in both groups. BCVA negatively correlated with nearly all MRDQ domains. While EZA showed a negative correlation in both groups, it was significant only in RP without CME. In the CME group, centrally located, outer nuclear layer-involving and large CS were associated with worse BCVA but better EZA.ConclusionMRDQ responses strongly correlated with clinical parameters. CME does not seem to affect self-reported visual function in RP patients, and CS may not worsen visual function. Thus, aggressive treatment of CME in RP may not be necessary.

OCT analysis and MPOD assessment in patients affected by retinitis pigmentosa

This study aimed to analyze Optical Coherence Tomography (OCT) parameters and Macular Pigment Optical Density (MPOD) changes in patients affected by Retinitis pigmentosa (RP). Eighteen eyes of 18 patients suffering from early-stage RP were enrolled in our observational study. 18 eyes of 18 patients age and gender matched were enrolled as controls. Patients were analyzed at baseline by undergoing complete baseline ophthalmologic examination, Spectral-domain Optical Coherence Tomography (OCT), Electroretinogram (ERG) and Heterochromatic Flicker Photometry (HFP). Main outcome measures were Macular Pigment Optical Density (MPOD), Central macular thickness (CMT), Central Choroidal Thickness (CCT) and Choroidal Vascularity Index (CVI). Lower CCT (p = 0.006), CVI (p < 0.001) and MPOD levels (p = 0.038) were found in affected patients, whereas higher CMT was detected in cases compared to healthy controls. Correlation analysis revealed the presence of a negative correlation between BCVA and Age and CMT and BCVA and a positive correlation between CCT and MPOD and CVI and CCT. Retinal and choroidal variations occur in patients affected by early-stage RP regarding functional and anatomical changes.

TENT5A mediates the cancer-inhibiting effects of EGR1 by suppressing the protein stability of RPL35 in hepatocellular carcinoma.

Terminal nucleotidyltransferase 5A (TENT5A), recently predicted as a non-canonical poly(A) polymerase, is critically involved in several human disorders including retinitis pigmentosa, cancer and obesity. However, the exact biological role of TENT5A in hepatocellular carcinoma (HCC) has not been elucidated. The transcription level of TENT5A and clinical correlation were analyzed using the LIRI-JP cohort, the TCGA-LIHC cohort, and clinical tissue samples of HCC patients in our laboratory. Proliferation, migration, and invasion were detected with stably TENT5A overexpressing and knockdown HCC cells in vitro and in vivo. Chromatin immunoprecipitation and dual-luciferase reporter assay were performed to verify the binding of the target protein to DNA. Co-immunoprecipitation and GST pull-down assay combined with mass spectrometry (MS) were used to identify protein interactions. Our study presented here shows that TENT5A is downregulated in HCC tissues, suggesting a shorter overall survival for patients. Gain- and loss-of-function experiments reveal that TENT5A suppresses the proliferation and metastasis, and the residue Gly122 is of great importance to the role of TENT5A in HCC. More importantly, EGR1 (Early growth response 1) directly binds to the TENT5A promoter and promotes TENT5A expression. By interacting with RPL35, TENT5A is involved in ribosome biogenesis and exerts a negative regulatory effect on the mTOR pathway. Our findings illustrate the role of the oncosuppressive function of TENT5A in HCC and suggest that the EGR1/TENT5A/RPL35 regulatory axis may be a promising target for therapeutic strategies in HCC.

Prevalence of Molecular Diagnoses for Usher Syndrome and the Need for Coordinated Care.

Usher syndrome (USH) is a rare, autosomal-recessive genetic disorder and a leading cause of early onset deaf-blindness. A clinical diagnosis is made by the presence of retinitis pigmentosa (RP) with sensorineural hearing loss (SNHL). Subtype (USH1, USH2, USH3) is determined by severity and age of onset. Molecular testing is able to further distinguish USH subtypes by causative gene. As gene therapy strategies continue to be explored for USH, it is important to know the underlying genetic cause and to coordinate care among an interdisciplinary team. We reviewed charts of 198 individuals presenting to the RP clinic at Bascom Palmer Eye Institute (BPEI) for suspected USH. Demographic information, USH clinical diagnosis, molecular testing, molecular diagnosis, and audiological data were collected. Of the 198 patients reviewed, 190 (96%) met clinical criteria for USH and received a clinical diagnosis. There were 67 (35%) that had a genetic test with a pathogenic molecular diagnosis. The average ages at molecular diagnosis were USH1B, 20 years old; USH2A, 37 years old; USH2C, 50 years old. Of the 67 with a molecular diagnosis, 23 (34%) established ophthalmic care and 8 of these (11%) established audiological care. Molecular testing and diagnosis should be part of the routine care of USH individuals to facilitate earlier interventions and coordinated care between ophthalmology and audiology. 4 Laryngoscope, 2024.