Treatments for dry age-related macular degeneration: therapeutic avenues, clinical trials and future directions

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the developed world. The identification of the central role of vascular endothelial growth factor (VEGF) in the pathogenesis of neovascular AMD and the introduction of anti-VEGF agents as gold-standard treatment, have drastically changed its prognosis-something yet to be seen in dry AMD. Several therapeutic avenues with a wide variability of targets are currently being investigated in dry AMD. The approaches being investigated to reduce the rate of disease progression include, (1) drugs with antioxidative properties, (2) inhibitors of the complement cascade, (3) neuroprotective agents, (4) visual cycle inhibitors, (5) gene therapy and (6) cell-based therapies. A number of early phase clinical trials have provided promising results, with many more ongoing and anticipated in the near future. In this review, we aim to provide an update of the interventional trials to date and future prospects for the treatment of dry AMD

Leber congenital amaurosis/early-onset severe retinal dystrophy: current management and clinical trials

Leber congenital amaurosis (LCA) is a severe congenital/early-onset retinal dystrophy. Given its monogenic nature and the immunological and anatomical privileges of the eye, LCA has been particularly targeted by cutting-edge research. In this review, we describe the current management of LCA, and highlight the clinical trials that are on-going and planned. RPE65-related LCA pivotal trials, which culminated in the first Food and Drug Administration-approved and European Medicines Agency-approved ocular gene therapy, have paved the way for a new era of genetic treatments in ophthalmology. At present, multiple clinical trials are available worldwide applying different techniques, aiming to achieve better outcomes and include more genes and variants. Genetic therapy is not only implementing gene supplementation by the use of adeno-associated viral vectors, but also clustered regularly interspaced short palindromic repeats (CRISPR)-mediated gene editing and post-transcriptional regulation through antisense oligonucleotides. Pharmacological approaches intending to decrease photoreceptor degeneration by supplementing 11-cis-retinal and cell therapy's aim to replace the retinal pigment epithelium, providing a trophic and metabolic retinal structure, are also under investigation. Furthermore, optoelectric devices and optogenetics are also an option for patients with residual visual pathway. After more than 10 years since the first patient with LCA received gene therapy, we also discuss future challenges, such as the overlap between different techniques and the long-term durability of efficacy. The next 5 years are likely to be key to whether genetic therapies will achieve their full promise, and whether stem cell/cellular therapies will break through into clinical trial evaluation

Functional evaluation in inherited retinal disease.

Functional assessments are a fundamental part of the clinical evaluation of patients with inherited retinal diseases (IRDs). Their importance and impact have become increasingly notable, given the significant breadth and number of clinical trials and studies investigating multiple avenues of intervention across a wide range of IRDs, including gene, pharmacological and cellular therapies. Moreover, the fact that many clinical trials are reporting improvements in vision, rather than the previously anticipated structural stability/slowing of degeneration, makes functional evaluation of primary relevance. In this review, we will describe a range of methods employed to characterise retinal function and functional vision, beginning with tests variably included in the clinic, such as visual acuity, electrophysiological assessment and colour discrimination, and then discussing assessments often reserved for clinical trials/research studies such as photoaversion testing, full-field static perimetry and microperimetry, and vision-guided mobility testing; addressing perimetry in greatest detail, given it is commonly a primary outcome metric. We will focus on how these tests can help diagnose and monitor particular genotypes, also noting their limitations/challenges and exploring analytical methodologies for better exploiting functional measurements, as well as how they facilitate patient inclusion and stratification in clinical trials and serve as outcome measures

Structural evaluation in inherited retinal diseases.

Ophthalmic genetics is a field that has been rapidly evolving over the last decade, mainly due to the flourishing of translational medicine for inherited retinal diseases (IRD). In this review, we will address the different methods by which retinal structure can be objectively and accurately assessed in IRD. We review standard-of-care imaging for these patients: colour fundus photography, fundus autofluorescence imaging and optical coherence tomography (OCT), as well as higher-resolution and/or newer technologies including OCT angiography, adaptive optics imaging, fundus imaging using a range of wavelengths, magnetic resonance imaging, laser speckle flowgraphy and retinal oximetry, illustrating their utility using paradigm genotypes with on-going therapeutic efforts/trials

Coats-like Vasculopathy in Inherited Retinal Disease: Prevalence, Characteristics, Genetics, and Management

Purpose: To describe the largest, most phenotypically and genetically diverse cohort of patients with inherited retinal disease (IRD)-related Coats-like vasculopathy (CLV). Design: Multicenter retrospective cohort study. Participants: A total of 67 patients with IRD-related CLV. Methods: Review of clinical notes, ophthalmic imaging, and molecular diagnosis from 2 international centers. Main Outcome Measures: Visual function, retinal imaging, management, and response to treatment were evaluated and correlated. Results: The prevalence of IRD-related CLV was 0.5%; 54% of patients had isolated retinitis pigmentosa (RP), 21% had early-onset severe retinal dystrophy, and less frequent presentations were syndromic RP, sector RP, cone-rod dystrophy, achromatopsia, PAX6-related dystrophy, and X-linked retinoschisis. The overall age of patients at CLV diagnosis was 30.7 ± 16.9 years (1–83). Twenty-one patients (31%) had unilateral CLV, and the most common retinal features were telangiectasia, exudates, and exudative retinal detachment (ERD) affecting the inferior and temporal retina. Macular edema/schisis was observed in 26% of the eyes, and ERD was observed in 63% of the eyes. Fifty-four patients (81%) had genetic testing, 40 of whom were molecularly solved. Sixty-six eyes (58%) were observed, 17 eyes (15%) were treated with a single modality, and 30 eyes (27%) had a combined approach. Thirty-five eyes (31%) were “good responders,” 42 eyes (37%) were “poor responders,” 22 eyes (19%) had low vision at baseline and were only observed, and 12 eyes (11%) did not have longitudinal assessment. Twenty-one observed eyes (62%) responded well versus 14 (33%) treated eyes. Final best-corrected visual acuity was significantly worse than baseline (P = 0.002); 40 patients (60%) lost 15 ETDRS letters or more over follow-up in 1 or both eyes, and 21 patients (31%) progressed to more advanced stages of visual impairment. Conclusions: Inherited retinal disease–related CLV is rare, sporadic, and mostly bilateral; there is no gender predominance, and it can occur in diverse types of IRD at any point of the disease, with a mean onset in the fourth decade of life. Patients with IRD-related CLV who have decreased initial visual acuity, ERD, CLV changes affecting 2 or more retinal quadrants, and CRB1-retinopathy may be at higher risk of a poor prognosis. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article

Detailed Clinical, Ophthalmic, and Genetic Characterization of ADGRV1-Associated Usher Syndrome

Purpose: To present the clinical characteristics, retinal features, natural history, and genetics of ADGRV1-Usher syndrome (USH). Design: Multicenter international retrospective cohort study. Methods: Clinical notes, hearing loss history, multimodal retinal imaging, and molecular diagnosis were reviewed. Thirty patients (28 families) with USH type 2 and disease-causing variants in ADGRV1 were identified. Visual function, retinal imaging, and genetics were evaluated and correlated, with retinal features also compared with those of the commonest cause of USH type 2, USH2A-USH. Results: The mean age at the first visit was 38.6 ± 12.0 years (range: 19-74 years), and the mean follow-up time was 9.0 ± 7.7 years. Hearing loss was reported in the first decade of life by all patients, 3 (10%) described progressive loss, and 93% had moderate-severe impairment. Visual symptom onset was at 17.0 ± 7.7 years of age (range: 6-32 years), with 13 patients noticing problems before the age of 16. At baseline, 90% of patients had no or mild visual impairment. The most frequent retinal features were a hyperautofluorescent ring at the posterior pole (70%), perimacular patches of decreased autofluorescence (59%), and mild-moderate peripheral bone-spicule–like deposits (63%). Twenty-six (53%) variants were previously unreported, 19 families (68%) had double-null genotypes, and 9 were not-double-null. Longitudinal analysis showed significant differences between baseline and follow-up central macular thickness (−1.25 µm/y), outer nuclear layer thickness (−1.19 µm/y), and ellipsoid zone width (−40.9 µm/y). The rate of visual acuity decline was 0.02 LogMAR (1 letter)/y, and the rate of constriction of the hyperautofluorescent ring was 0.23 mm2/y. Conclusions: ADGRV1-USH is characterized by early-onset, usually non-progressive, mild-to-severe hearing loss and generally good central vision until late adulthood. Perimacular atrophic patches and relatively retained ellipsoid zone and central macular thickness in later adulthood are more often seen in ADGRV1-USH than in USH2A-USH

Clinical and genetic characterization of RDH12-retinal dystrophy in a South American cohort

Purpose: To characterize the largest cohort of individuals with RDH12-retinal dystrophy to date, and the first one from South America. // Design: Retrospective multicenter international study. // Subjects: 78 patients (66 families) with an inherited retinal dystrophy and biallelic variants in RDH12. // Methods: Review of clinical notes, ophthalmic images, and molecular diagnosis. // Main outcome measures: Visual function, retinal imaging and characteristics were evaluated and correlated. // Results: Thirty-seven individuals self-identified as Latino (51%) and 34 as White (47%). Mean age at the baseline visit was 19.8 ± 13 years old (6 months – 46 years old, median 18.5); 41 (53%) were children. Thirty-nine patients (50%) had subsequent visits, with mean follow-up of 6.8 + 7.3 years (0 – 29). Sixty-nine individuals (88%) had Leber congenital amaurosis/early onset severe retinal dystrophy (LCA/EOSRD). Macular and mid-peripheral atrophy was seen in all patients from 3 years of age. A novel retinal finding was a hyperautofluorescent ring in 2 young children with LCA. Eight variants (21%) were previously unreported and the most frequent variant was c.295C>A, p.Leu99Ile, present in 52 alleles of 32 probands. Individuals with LCA homozygous for p.Leu99Ile (31%) had a later age of onset, slower rate of BCVA decrease, the largest percentage of patients with mild visual impairment, and were predicted to reach legal blindness at an older age than the rest of the cohort. // Conclusions: By describing the largest molecularly confirmed cohort to date, improved understanding of disease progression was possible. Our detailed characterization aims to support research and the development of novel therapies that may have the potential to reduce or prevent vision loss in individuals with RDH12-associated retinal dystrophy

Multi-disciplinary team directed analysis of whole genome sequencing reveals pathogenic non-coding variants in molecularly undiagnosed inherited retinal dystrophies

PURPOSE: To identify, using genome sequencing (GS), likely pathogenic non-coding variants in inherited retinal dystrophy (IRD) genes Methods: Patients with IRD were recruited to the study and underwent comprehensive ophthalmological evaluation and GS. The results of GS were investigated through virtual gene panel analysis and plausible pathogenic variants and clinical phenotype evaluated by multi-disciplinary team (MDT) discussion. For unsolved patients in whom a specific gene was suspected to harbour a missed pathogenic variant, targeted re-analysis of non-coding regions was performed on GS data. Candidate variants were functionally tested including by mRNA analysis, minigene and luciferase reporter assays. RESULTS: Previously unreported, likely pathogenic, non-coding variants, in 7 genes (PRPF31, NDP, IFT140, CRB1, USH2A, BBS10, and GUCY2D), were identified in 11 patients. These were shown to lead to mis-splicing (PRPF31, IFT140, CRB1, USH2A) or altered transcription levels (BBS10, GUCY2D). CONCLUSION: MDT-led, phenotype driven, non-coding variant re-analysis of GS is effective in identifying missing causative alleles

Can artificial intelligence accelerate the diagnosis of inherited retinal diseases? Protocol for a data-only retrospective cohort study (Eye2Gene)

INTRODUCTION: Inherited retinal diseases (IRD) are a leading cause of visual impairment and blindness in the working age population. Mutations in over 300 genes have been found to be associated with IRDs and identifying the affected gene in patients by molecular genetic testing is the first step towards effective care and patient management. However, genetic diagnosis is currently slow, expensive and not widely accessible. The aim of the current project is to address the evidence gap in IRD diagnosis with an AI algorithm, Eye2Gene, to accelerate and democratise the IRD diagnosis service. METHODS AND ANALYSIS: The data-only retrospective cohort study involves a target sample size of 10 000 participants, which has been derived based on the number of participants with IRD at three leading UK eye hospitals: Moorfields Eye Hospital (MEH), Oxford University Hospital (OUH) and Liverpool University Hospital (LUH), as well as a Japanese hospital, the Tokyo Medical Centre (TMC). Eye2Gene aims to predict causative genes from retinal images of patients with a diagnosis of IRD. For this purpose, 36 most common causative IRD genes have been selected to develop a training dataset for the software to have enough examples for training and validation for detection of each gene. The Eye2Gene algorithm is composed of multiple deep convolutional neural networks, which will be trained on MEH IRD datasets, and externally validated on OUH, LUH and TMC. ETHICS AND DISSEMINATION: This research was approved by the IRB and the UK Health Research Authority (Research Ethics Committee reference 22/WA/0049) 'Eye2Gene: accelerating the diagnosis of IRDs' Integrated Research Application System (IRAS) project ID: 242050. All research adhered to the tenets of the Declaration of Helsinki. Findings will be reported in an open-access format