Long-term visual and microperimetry outcomes following autologous retinal pigment epithelium choroid graft for neovascular age-related macular degeneration

To describe the 2- to 4-year visual and microperimetry outcomes of autologous retinal pigment epithelium (RPE)-choroid graft in patients with neovascular age-related macular degeneration (AMD).In this retrospective cohort study, 12 patients with subfoveal neovascular AMD who had undergone autologous RPE-choroid graft between August 2004 and June 2005 were reviewed. Change in visual acuity (VA), contrast sensitivity (CS), fixation stability and retinal sensitivity on microperimetry after 2-3 years and the rates of late postoperative complications were examined.Patients were followed for 26-48 months (mean, 39). Median preoperative VA (logMAR) was 0.87 but declined to 1.43 (1 year), 1.46 (2 years) and 1.38 (3 years), P = 0.001. Median CS (logCS) was 0.75 preoperatively but declined to 0.45 at 2 years. Six patients had serial microperimetry. Fixation stability declined in 1 but improved in 2 patients. All 6 had decline in retinal sensitivity over the graft during follow up. Retinal detachment did not occur after 12 months but 8 developed epiretinal membrane, 12 had cystic retinal change over the graft and 4 developed recurrent choroidal neovascularization. However, 10 grafts retained autofluorescence signal at 18-48 months of follow up.Autologous RPE-choroid graft can maintain VA, stable fixation and retinal sensitivity in some patients for over 3 years. The spatial correlation between graft autofluorescence, outer retinal structures on optical coherence tomography and retinal sensitivity are consistent with photoreceptor cell rescue. However, we caution the use of this technique as there is high complication rate and delayed loss of retinal function

Envisioning the development of a CRISPR-Cas mediated base editing strategy for a patient with a novel pathogenic CRB1 single nucleotide variant

Background Inherited retinal degeneration (IRD) associated with mutations in the Crumbs homolog 1 (CRB1) gene is associated with a severe, early-onset retinal degeneration for which no therapy currently exists. Base editing, with its capability to precisely catalyse permanent nucleobase conversion in a programmable manner, represents a novel therapeutic approach to targeting this autosomal recessive IRD, for which a gene supplementation is challenging due to the need to target three different retinal CRB1 isoforms. Purpose To report and classify a novel CRB1 variant and envision a possible therapeutic approach in form of base editing. Methods Case report. Results A 16-year-old male patient with a clinical diagnosis of early-onset retinitis pigmentosa (RP) and characteristic clinical findings of retinal thickening and coarse lamination was seen at the Oxford Eye Hospital. He was found to be compound heterozygous for two CRB1 variants: a novel pathogenic nonsense variant in exon 9, c.2885T>A (p.Leu962Ter), and a likely pathogenic missense change in exon 6, c.2056C>T (p.Arg686Cys). While a base editing strategy for c.2885T>A would encompass a CRISPR-pass mediated “read-through” of the premature stop codon, the resulting missense changes were predicted to be “possibly damaging” in in-silico analysis. On the other hand, the transversion missense change, c.2056C>T, is amenable to transition editing with an adenine base editor (ABE) fused to a SaCas9-KKH with a negligible chance of bystander edits due to an absence of additional Adenines (As) in the editing window. Conclusions This case report records a novel pathogenic nonsense variant in CRB1 and gives an example of thinking about a base editing strategy for a patient compound heterozygous for CRB1 variants

Transcorneal electrical stimulation for the treatment of retinitis pigmentosa: results from the TESOLAUK trial

OBJECTIVE: To explore the impact of weekly transcorneal electrical stimulation (TES) over a 6-month period as a treatment for retinitis pigmentosa (RP). METHODS AND ANALYSIS: A prospective open-label observational trial was carried out assessing weekly TES in participants with RP for a period of 6 months followed by observation for a further 6 months. Clinical examination and investigations were carried out at 3 monthly intervals for a total of 12 months. The primary outcome measure explored safety through a descriptive analysis of adverse effects with secondary outcome measures evaluating structural and functional efficacy. RESULTS: Seven male and seven female participants with RP aged 18-80 years were recruited. TES was well tolerated with no serious adverse events reported. Two participants reported transient foreign body sensation and one participant had discomfort underneath the skin electrode. Following 6 months of TES, best-corrected visual acuity increased by 1.1±1.4 letters in the control arm and 0.93±1.4 letters in the treated arm. Central microperimetry threshold sensitivity rose by 0.02±0.5 decibels (dB) and 0.37±0.4 dB and Goldmann visual field volume by 0.16±0.09 steradians (sr) vs 0.22±0.12 sr for the control and treated eye, respectively. There was no statistical significance seen between eyes following the treatment or observation period. CONCLUSION:: This small open-label clinical trial showed that TES was safe and well tolerated in patients with RP. Visual function measurements at 6 months demonstrated no significant difference between the control and treated eyes. The results justify a larger clinical trial over a longer period of time in order to identify any treatment effect

Longitudinal Study to Assess the Quantitative Use of Fundus Autofluorescence for Monitoring Disease Progression in Choroideremia

BACKGROUND: Characterisation of preserved autofluorescence (PAF) area in choroideremia (CHM) and its validity for monitoring disease progression in clinical trials is of importance. METHODS: Eighty patients with molecularly confirmed CHM were recruited. PAF area was measured manually by 2 graders and half-life was calculated based on exponential decay model. RESULTS: Mean age at baseline and follow-up examination was 38.1 (range, 10-69) and 40.7 (range, 11-70) years. Mean follow-up interval was 29 months (range, 6-104). The median LogMAR visual acuity was 0.10 (OD) and 0.18 (OS). Interobserver repeatability for PAF area was -0.99 to 1.03 mm2 (-6.46 to 6.49% of area). There was a statistically significant relationship between age and rate of PAF area loss (r2 = 0.28, p = 0.012). The half-life for PAF area was 13.7 years (range, 1.7-216.0 years). The correlation between half-life and age was stronger than between half-life and log transformed baseline PAF area, although neither was statistically significant. CONCLUSIONS: The intra- and inter-observer PAF area measurement variability provides a baseline change, which must be overcome in a clinical trial if this metric were to be used. Treatments must slow progression to alter the exponential decay in a timely manner accounting for naturally slow progression patterns

Longitudinal Study to Assess the Quantitative Use of Fundus Autofluorescence for Monitoring Disease Progression in Choroideremia

BACKGROUND: Characterisation of preserved autofluorescence (PAF) area in choroideremia (CHM) and its validity for monitoring disease progression in clinical trials is of importance. METHODS: Eighty patients with molecularly confirmed CHM were recruited. PAF area was measured manually by 2 graders and half-life was calculated based on exponential decay model. RESULTS: Mean age at baseline and follow-up examination was 38.1 (range, 10-69) and 40.7 (range, 11-70) years. Mean follow-up interval was 29 months (range, 6-104). The median LogMAR visual acuity was 0.10 (OD) and 0.18 (OS). Interobserver repeatability for PAF area was -0.99 to 1.03 mm2 (-6.46 to 6.49% of area). There was a statistically significant relationship between age and rate of PAF area loss (r2 = 0.28, p = 0.012). The half-life for PAF area was 13.7 years (range, 1.7-216.0 years). The correlation between half-life and age was stronger than between half-life and log transformed baseline PAF area, although neither was statistically significant. CONCLUSIONS: The intra- and inter-observer PAF area measurement variability provides a baseline change, which must be overcome in a clinical trial if this metric were to be used. Treatments must slow progression to alter the exponential decay in a timely manner accounting for naturally slow progression patterns

“Genetic and clinical findings in an ethnically diverse retinitis pigmentosa cohort associated with pathogenic variants in EYS”

Background and objectives: The EYS gene is an important cause of autosomal recessive retinitis pigmentosa (arRP). The objective of this study is to report on novel pathogenic variants in EYS and the range of associated phenotypes. / Subjects and methods: This retrospective case series at a tertiary referral centre for inherited retinal diseases describes patients with an IRD and at least two variants in the EYS gene. Phenotyping included multimodal retinal imaging; genotyping molecular genetic analysis using targeted next generation sequencing. Sanger sequencing verification and analysis of novel variants using in silico approaches to determine their predicted pathogenicity. / Results: Eight male and four female patients were included. Age at onset ranged from 11 to 62 years with variable symptom presentation; ten patients showed classical features of retinitis pigmentosa, albeit with great variation in disease severity and extent. Two patients had atypical phenotypes: one with localised inferior sector pigmentation and a mild RP phenotype with changes predominantly at the posterior pole. Eighteen variants in EYS were identified, located across the gene: six were novel. Eight variants were missense, two altered splicing, one was a whole exon duplication and the remainder were predicted to result in premature truncation of the protein. / Conclusion: The marked variability in severity and age of onset in most patients in this ethnically diverse cohort adds to growing evidence that that mild phenotypes are associated with EYS variants. Similarly, the two atypical cases add to the growing diversity of EYS disease as do the six novel pathogenic variants described

ON-bipolar cell gene expression during retinal degeneration: Implications for optogenetic visual restoration.

PURPOSE: Retinal bipolar cells survive even in the later stages of inherited retinal degenerations (IRDs) and so are attractive targets for optogenetic approaches to vision restoration. However, it is not known to what extent the remodelling that these cells undergo during degeneration affects their function. Specifically, it is unclear if they are free from metabolic stress, receptive to adeno-associated viral vectors, suitable for opsin-based optogenetic tools and able to propagate signals by releasing neurotransmitter. METHODS: Fluorescence activated cell sorting (FACS) was performed to isolate labelled bipolar cells from dissociated retinae of litter-mates with or without the IRD mutation Pde6brd1/rd1 selectively expressing an enhanced yellow fluorescent protein (EYFP) as a marker in ON-bipolar cells. Subsequent mRNA extraction allowed Illumina® microarray comparison of gene expression in bipolar cells from degenerate to those of wildtype retinae. Changes in four candidate genes were further investigated at the protein level using retinal immunohistochemistry over the course of degeneration. RESULTS: A total of sixty differentially expressed transcripts reached statistical significance: these did not include any genes directly associated with native primary bipolar cell signalling, nor changes consistent with metabolic stress. Four significantly altered genes (Srm2, Slf2, Anxa7 & Cntn1), implicated in synaptic remodelling, neurotransmitter release and viral vector entry had immunohistochemical staining colocalising with ON-bipolar cell markers and varying over the course of degeneration. CONCLUSION: Our findings suggest relatively few gene expression changes in the context of degeneration: that despite remodelling, bipolar cells are likely to remain viable targets for optogenetic vision restoration. In addition, several genes where changes were seen could provide a basis for investigations to enhance the efficacy of optogenetic therapies

The effectiveness of early lens extraction with intraocular lens implantation for the treatment of primary angle-closure glaucoma (EAGLE) : study protocol for a randomized controlled trial

Peer reviewedPublisher PD

Presynaptic partner selection during retinal circuit reassembly varies with timing of neuronal regeneration in vivo

Whether neurons can restore their original connectivity patterns during circuit repair is unclear. Taking advantage of the regenerative capacity of zebrafish retina, we show here the remarkable specificity by which surviving neurons reassemble their connectivity upon regeneration of their major input. H3 horizontal cells (HCs) normally avoid red and green cones, and prefer ultraviolet over blue cones. Upon ablation of the major (ultraviolet) input, H3 HCs do not immediately increase connectivity with other cone types. Instead, H3 dendrites retract and re-extend to contact new ultraviolet cones. But, if regeneration is delayed or absent, blue-cone synaptogenesis increases and ectopic synapses are made with red and green cones. Thus, cues directing synapse specificity can be maintained following input loss, but only within a limited time period. Further, we postulate that signals from the major input that shape the H3 HC's wiring pattern during development persist to restrict miswiring after damage