Retinal Dystrophy Associated With RLBP1 Retinitis Pigmentosa: A Five-Year Prospective Natural History Study.

Purpose: To assess the progression in functional and structural measures over a five-year period in patients with retinal dystrophy caused by RLBP1 gene mutation. Methods: This prospective, noninterventional study included patients with biallelic RLBP1 mutations from two clinical sites in Sweden and Canada. Key assessments included ocular examinations, visual functional measures (best-corrected visual acuity [BCVA], contrast sensitivity [CS], dark-adaptation [DA] kinetics up to six hours for two wavelengths [450 and 632 nm], Humphrey visual fields [HVF], full-field flicker electroretinograms), and structural ocular assessments. Results: Of the 45 patients enrolled, 38 completed the full five years of follow-up. At baseline, patients had BCVA ranging from -0.2 to 1.3 logMAR, poor CS, HVF defects, and prominent thinning in central foveal thickness. All patients had extremely prolonged DA rod recovery of approximately six hours at both wavelengths. The test-retest repeatability was high across all anatomic and functional endpoints. Cross-sectionally, poorer VA was associated with older age (right eye, correlation coefficient [CC]: 0.606; left eye, CC: -0.578; P < 0.001) and HVF MD values decreased with age (right eye, CC: -0.672, left eye, CC: -0.654; P < 0.001). However, no major changes in functional or structural measures were noted longitudinally over the five-year period. Conclusions: This natural history study, which is the first study to monitor patients with RLBP1 RD for five years, showed that severely delayed DA sensitivity recovery, a characteristic feature of this disease, was observed in all patients across all age groups (17-69 years), making it a potentially suitable efficacy assessment for gene therapy treatment in this patient population.

Qualitative exploration of the visual function impairments and impacts on vision-dependent activities of daily living in Retinitis Pigmentosa and Leber Congenital Amaurosis: content validation of the ViSIO-PRO and ViSIO-ObsRO measures.

BACKGROUND: Retinitis Pigmentosa (RP) and Leber Congenital Amaurosis (LCA) are rare inherited retinal degenerative disorders. The associated visual impairments have significant impacts on patients' vision-dependent activities of daily living (ADL), mobility, and distal health-related quality of life (HRQoL). To adequately capture patient and caregiver perspectives in clinical trials, patient and observer-reported outcome instruments must demonstrate sufficient evidence of content validity in the target population. This study aimed to explore the patient experience of RP/LCA and assess the content validity of the Visual Symptom and Impact Outcomes PRO (ViSIO-PRO) and ObsRO (ViSIO-ObsRO) instruments in RP/LCA. METHODS: A total of 66 qualitative, combined concept elicitation (CE) and cognitive debriefing (CD) interviews were conducted (33 adults, 10 adolescents, 8 children and 15 caregivers of children) in the US, France, Germany, and Canada. Patients had a clinical and genetic diagnosis of RP/LCA from a range of genotypes. CE results were used to further inform the development of a conceptual model and CD interviews assessed the relevance and understanding of the 44-item ViSIO-PRO and 26-item ViSIO-ObsRO instruments. Interviews were conducted across two iterative rounds to allow item modifications. RESULTS: Findings were consistent across RP/LCA genotypes. Night blindness, reduced peripheral vision, vision in very bright lighting and light/dark adaptation were the most frequently reported visual function symptoms impacting vision-dependent ADL and mobility. Impacts on distal HRQoL domains were also reported. The ViSIO-PRO and ObsRO items were well understood by participants and relevant across genotypes. The instructions, 7-day recall period and response scales were well understood and endorsed. Participant and expert clinician feedback supported modifications to item wording, the addition of six new ViSIO-PRO items and one new ViSIO-ObsRO item, and the removal of one ViSIO-PRO item due to lack of relevance. CONCLUSIONS: Findings support the content validity of the ViSIO-PRO and ViSIO-ObsRO instruments for use across RP/LCA genotypes. Ongoing research to evaluate the psychometric validity of the instruments will support future use of the instruments as efficacy endpoints in clinical trials and in general clinical practice to track disease severity and impact of disease on functioning.

Development of Novel Patient-Reported Outcome (PRO) and Observer-Reported Outcome (ObsRO) Instruments in Retinitis Pigmentosa (RP) and Leber Congenital Amaurosis (LCA): ViSIO-PRO and ViSIO-ObsRO.

INTRODUCTION: Retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) are rare inherited retinal degenerative disorders resulting in visual impairments and impacts on patients' vision-dependent activities of daily living (ADL), mobility and distal health-related quality of life (HRQoL). This study aimed to conduct qualitative research to understand the patient experience of RP/LCA across genotypes and inform development of patient- and observer-reported outcome (PRO/ObsRO) instruments in RP/LCA. METHODS: Research activities included a qualitative literature review and review of existing visual function PRO instruments in RLBP1 RP, and concept elicitation (CE) and cognitive debriefing (CD) interviews of existing PRO instruments with patients with RLBP1 RP, expert clinicians, and payers. In wider RP/LCA, a social media listening (SML) study and a qualitative literature review was conducted, while psychometric evaluation of a PRO instrument in LCA was performed. Input from expert clinicians was sought at key stages. RESULTS: Findings from the qualitative literature reviews identified a range of visual function symptoms which had significant impacts on patients' vision-related ADL and distal HRQoL. Patient interviews identified additional visual function symptoms and impacts not previously reported in published literature. These sources informed development and refinement of a conceptual model displaying the patient experience of RP/LCA. Review of existing visual function PRO instruments, and CD interviews evaluating their content validity, confirmed that no existing instrument provides a comprehensive assessment of all concepts relevant to patients with RP/LCA. This highlighted the need for development of the Visual Symptom and Impact Outcomes PRO and ObsRO instruments to adequately assess the patient experience of RP/LCA. CONCLUSIONS: Results informed and supported development of the instruments to assess visual functioning symptoms and vision-dependent ADL, mobility and distal HRQoL in RP/LCA, in accordance with regulatory standards. Next steps to further support use in RP/LCA clinical trials/practice includes content and psychometric validation of the instruments in this population.

Gene therapy for inherited retinal disease: long-term durability of effect.

The recent approval of voretigene neparvovec (Luxturna®) for patients with biallelic RPE65 mutation-associated inherited retinal dystrophy with viable retinal cells represents an important step in the development of ocular gene therapies. Herein, we review studies investigating the episomal persistence of different recombinant adeno-associated virus (rAAV) vector genomes and the pre-clinical and clinical evidence of long-term effects of different RPE65 gene replacement therapies. A targeted review of articles published between 1974 and January 2021 in Medline®, Embase®, and other databases, was conducted, followed by a descriptive longitudinal analysis of the clinical trial outcomes of voretigene neparvovec. Following an initial screening, 14 publications examining the episomal persistence of different rAAV genomes and 71 publications evaluating gene therapies in animal models were included. Viral genomes were found to persist for at least 22 months (longest study follow-up) as transcriptionally active episomes. Treatment effects lasting almost a decade were reported in canine disease models, with more pronounced effects the earlier the intervention. The clinical trial outcomes of voretigene neparvovec are consistent with pre-clinical findings and reveal sustained results for up to 7.5 years for the full-field light sensitivity threshold test and 5 years for the multi-luminance mobility test in the Phase I and Phase III trials, respectively. In conclusion, the therapeutic effect of voretigene neparvovec lasts for at least a decade in animal models and 7.5 years in human subjects. Since retinal cells can retain functionality over their lifetime after transduction, these effects may be expected to last even longer in patients with a sufficient number of outer retinal cells at the time of intervention.

Epidemiology of Mutations in the 65-kDa Retinal Pigment Epithelium (RPE65) Gene-Mediated Inherited Retinal Dystrophies: A Systematic Literature Review.

INTRODUCTION: Inherited retinal dystrophies (IRDs) represent a genetically diverse group of progressive, visually debilitating diseases. Adult and paediatric patients with vision loss due to IRD caused by biallelic mutations in the 65-kDa retinal pigment epithelium (RPE65) gene are often clinically diagnosed as retinitis pigmentosa (RP), and Leber congenital amaurosis (LCA). This study aimed to understand the epidemiological landscape of RPE65 gene-mediated IRD through a systematic review of the literature, as the current evidence base for its epidemiology is very limited. METHODS: Medline, Embase, and other databases were searched for articles on the epidemiology of RPE65 gene-mediated IRDs from inception until June 2021. Studies were included if they were original research articles reporting the epidemiology of RP and LCA and/or proportion of RPE65 gene mutations in these clinically diagnosed or molecularly confirmed IRDs patients. RESULTS: A total of 100 studies with relevant data were included in this systematic review. The range for prevalence of LCA and RP in the literature was 1.20-2.37 and 11.09-26.43 per 100,000, respectively. The proportion of RPE65 mutations in clinically diagnosed patients with LCA was found to be between ~ 2-16% within the US and major European countries (France, Germany, Italy, Spain, and the UK). This range was also comparable to our findings in the Asian region for RPE65-LCA (1.26-16.67%). Similarly, for these European countries, RPE65-RP was estimated between 0.23 and 1.94%, and RPE65-IRD range was 1.2-14%. Further, in the Americas region, mutations in RPE65 were reported to cause 1-3% of RP and 0.8-3.7% of IRD cases. Lastly, the RPE65-IRD range was 4.81-8% in the Middle East region. CONCLUSIONS: There are significant variations in reporting of RPE65 proportions within countries as well as regions. Generating robust epidemiological evidence on RPE65 gene-mediated IRDs would be fundamental to support rare disease awareness, timely therapeutic intervention, and public health decision-making.

Qualitative Interviews to Better Understand the Patient Experience and Evaluate Patient-Reported Outcomes (PRO) in RLBP1 Retinitis Pigmentosa (RLBP1 RP).

INTRODUCTION: RLBP1 RP is an autosomal recessive form of retinitis pigmentosa (RP), characterized by night blindness, prolonged dark adaptation, constricted visual fields and impaired macular function. This study aimed to better understand the patient experience of RLBP1 RP and evaluate the content validity of existing patient reported outcome (PRO) instruments in this condition. METHODS: Semi-structured concept elicitation and cognitive debriefing interviews were conducted with RLBP1 RP patients in Canada and Sweden. Interviews started with open-ended concept elicitation questioning, and then patients were cognitively debriefed on The National Eye Institute Visual Functioning Questionnaire (NEI VFQ-25), the Low Luminance Questionnaire (LLQ) and four light/dark adaptation items of the Visual Activities Questionnaire (VAQ). Qualitative interviews were also conducted with three expert clinicians. Anonymized, verbatim transcripts were analyzed using thematic analysis. RESULTS: Twenty-one patients were interviewed (Canada n = 10; Sweden n = 11). Symptoms reported included night blindness (n = 21), difficulty adapting to changes in lighting (n = 21) and difficulties seeing in bright lighting (n = 18). Patients experienced substantial impacts on daily activities (n = 21) and physical functioning (n = 17). Patients had difficulty interpreting and selecting a response for some items in the NEI VFQ-25 and LLQ. Some items were not relevant to patients' disease experience. There were both gaps and overlaps in the conceptual coverage of the instruments. CONCLUSIONS: Visual impairment due to RLBP1 RP has a substantial impact on physical functioning and daily activities. To adequately assess all important symptoms and associated functional impacts in RLBP1 RP, it is recommended to either modify one or more existing instruments or to develop a new non-syndromic RP specific instrument.

ASSESSMENT OF ANATOMICAL AND FUNCTIONAL OUTCOMES WITH OCRIPLASMIN TREATMENT IN PATIENTS WITH VITREOMACULAR TRACTION WITH OR WITHOUT MACULAR HOLES: Results of OVIID-1 Trial.

PURPOSE: To evaluate the anatomical and functional outcomes with ocriplasmin in patients with vitreomacular traction (VMT) with or without macular hole (MH). METHODS: In a Phase 4, multicenter, single-arm, open-label study, eligible patients (VMT with focal adhesion, without epiretinal membrane, and with MH ≤400 µm [if present]) received a single intravitreal injection of ocriplasmin. Nonsurgical resolution of VMT (Day 28 [primary endpoint]), best-corrected visual acuity, MH closure, vitrectomy rate, and safety were assessed through Day 180. RESULTS: Overall, 466 patients were included in the full analysis set, of whom 47.4% had VMT resolution by Day 28; resolution rates in patients with VMT without MH, VMT with MH ≤250 µm, and VMT with MH >250 to ≤400 µm were 43.4%, 68.6%, and 62.7%, respectively. Macular hole closure was higher in eyes with VMT and MH ≤250 µm (57.1%) than in eyes with VMT and MH >250 to ≤400 µm (27.5%) at Day 28. Overall, 30.8% of patients with VMT resolution gained ≥10 letters in best-corrected visual acuity at Day 180. Adverse events were consistent with the known safety profile of ocriplasmin. CONCLUSION: Ocriplasmin is effective for resolution of VMT without or with MH (≤400 µm); treatment outcomes can be optimized with patient selection.

Resource Utilization Among Glaucoma Patients in the UK Treated with Beta-Blocker and Non-Beta-Blocker Adjunctive Therapy: A Retrospective Cohort Analysis.

INTRODUCTION: Few studies have examined outcomes and potential complications among glaucoma patients who are prescribed topical beta-blockers. This study examined resource usage (number of GP visits and hospitalizations) and diagnoses of respiratory or cardiovascular conditions among glaucoma patients prescribed beta-blockers compared to patients not prescribed beta-blockers. METHODS: A retrospective cohort analysis was conducted using data from the UK Clinical Practice Research Datalink (CPRD) database over the period January 1, 2006 to March 31, 2014. Adult patients with at least one diagnosis of glaucoma were categorized into beta-blocker users and non-beta-blocker users. Beta-blocker users were further separated into patients that maintained beta-blocker therapy and patients that discontinued beta-blocker treatment in year 2 of the post-index period. The CPRD data was queried directly to obtain the number of GP visits, and hospitalizations were extracted by linking the CPRD and Hospital Episode Statistics (HES) patient-level data. RESULTS: In the 12 months after being prescribed beta-blockers, patients that later discontinued beta-blocker treatment had a significantly higher average number of hospitalizations than patients that maintained beta-blocker therapy and the non-beta-blocker users (p < 0.05). In the year after beta-blocker initiation, there was a statistically significant within-group difference pre- and post-beta-blocker initiation for all groups, but the greatest number of GP visits occurred in the patients that subsequently discontinued beta-blocker treatment (mean 19.27). Patients that discontinued beta-blocker treatment were significantly more likely to have cardiovascular events than non-beta-blocker users in the post-index period (p < 0.05). CONCLUSION: This study suggests that the introduction of beta-blockers in a certain group of patients who later discontinue their use is associated with increased use of medical resources (higher number of GP visits and hospitalizations) in glaucoma patients in the UK, which may be indicative of a potential relationship between use of topical beta-blockers in glaucoma therapy and adverse outcomes.

Correction of presbyopia with refractive multifocal phakic intraocular lenses.

PURPOSE: To evaluate the efficacy of and specify the conditions required for implantation of an anterior chamber multifocal phakic intraocular lens (IOL) to correct presbyopia. SETTING: Monticelli Clinic, Marseilles, France. METHOD: Fifty-five eyes of 33 patients (21 women, 12 men) had implantation of a foldable anterior chamber multifocal phakic IOL. The initial refraction was between -5.00 diopters (D) and +5.00 D. The IOL had an addition of +2.50 D. An uncorrected distance acuity of 0.6 or better (decimal scale) and an uncorrected near acuity (Parinaud scale) of 3 or better (Parinaud 2 approximately equal to Jaeger 1) was considered a successful postoperative result. RESULTS: The mean follow-up was 42.6 weeks +/- 18 (SD). Postoperatively, the mean refraction was -0.12 +/- 0.51 D, the mean decimal uncorrected distance acuity was 0.78 +/- 0.20, and the mean Parinaud uncorrected near acuity was 2.3 +/- 0.6. Eighty-four percent of eyes achieved an uncorrected distance acuity of 0.60 or better and an uncorrected near acuity of Parinaud 3 or better. The IOL was explanted in 4 eyes for different, but essentially optical, reasons. No significant anatomic complications were observed. CONCLUSIONS: Implantation of an anterior chamber multifocal phakic IOL to correct presbyopia was effective and gave good predictability. The procedure is reversible in cases of patient intolerance to the IOL, unwanted optical phenomena, or complications. Strict inclusion criteria should be used for patient selection.

Avaliação de um novo implante intra-orbitário: resultados preliminares / Evaluation of a new intraorbital implant: preliminary results

Objetivo: Apresentar novo tipo de implante orbitário, com formato original, o modo de utilização e os resultados clínicos preliminares. Métodos: Os autores descrevem a técnica cirúrgica utilizada para a inserção do novo implante em 22 pacientes, como implante primário ou secundário. Os pacientes foram avaliados de forma prospectiva quanto aos seguintes aspectos: cosmético (grau de sulco suprapalpebral e enoftalmia), mobilidade, centragem e volume do implante. O tempo de seguimento variou de 3 a 15 meses (média 1 ano). resultados: observou-se resultado cosmético satisfatório, sem caso de enoftalmia ou de sulco suprapalpebral importante, bem como boa mobilidade das próteses adaptadas sobre o novo implante. Não houve casos de infecção, migração ou extrusão do implante. Conclusão: Os resultados pós-operatórios com o novo implante são comparáveis aos implantes com pinos externos. Contudo um estudo multicêntrico, com maior tempo de controle pós-operatório é necessário, para avaliação mais acurada das complicações potenciais.

Uso da colagel na cirurgia da conjuntiva: estudo experimental / Use of colagel in conjunctival surgery: experimental study

Os autores estudaram reaçäo dos tecidos oculares produzida pela aplicaçäo da cola tecidual colagel (Cirumédica), com o intuito de avaliar a possibilidade da sua utilizaçäo na cirurgia de exerese do pterígeo com a técnica do transplante de conjuntiva. Doze coelhas foram submetidas a peritomia de base límbica com aplicaçäo de colagel sobre a esclera que foi recoberta pela conjuntiva. Três coelhas näo operadas compuseram o grupo controle. O sacrifício dos animais foi feito 3, 7, 15 e 30 dias após a cirurgia, procedendo-se a exenteraçäo orbitária e preparo do material para exame histológico. Após a inoculaçäo do adesivo, como intra-ocular, com predomínio de células polimorfonucleares. Com a evoluçäo, houve melhora aparente da inflamaçäo, com limitaçäo da reaçäo ao local da inoculaçäo; porém, a inflamaçäo de estruturas intra-oculares (irite, vitreite, coroidite) continuou, havendo necrose e perfuraçäo ocular próximo ao local da inoculaçäo em alguns animais. Pode-se concluir que a colagel näo se presta para o uso como adesivo tecidual nas cirurgias da conjuntiva