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Inherited retinal diseases (IRDs) have been in the front line of gene therapy development for the last decade, providing a useful platform to test novel therapeutic approaches. More than 40 clinical trials have been completed or are ongoing, tackling autosomal recessive and X-linked conditions, mostly through adeno-associated viral vector delivery of a normal copy of the disease-causing gene. However, only recently has autosomal dominant (ad) disease been targeted, with the commencement of a trial for rhodopsin ( RHO )-associated retinitis pigmentosa (RP), implementing antisense oligonucleotide (AON) therapy, with promising preliminary results (NCT04123626).Autosomal dominant RP represents 15%-25% of all RP, with RHO accounting for 20%-30% of these cases. Autosomal dominant macular and cone-rod dystrophies (MD/CORD) correspond to approximately 7.5% of all IRDs, and approximately 35% of all MD/CORD cases, with the main causative gene being BEST1 Autosomal dominant IRDs are not only less frequent than recessive, but also tend to be less severe and have later onset; for example, an individual with RHO -adRP would typically become severely visually impaired at an age 2-3 times older than in X-linked RPGR -RP.Gain-of-function and dominant negative aetiologies are frequently seen in the prevalent adRP genes RHO , RP1 and PRPF31 among others, which would not be effectively addressed by gene supplementation alone and need creative, novel approaches. Zinc fingers, RNA interference, AON, translational read-through therapy, and gene editing by clustered regularly interspaced short palindromic repeats/Cas are some of the strategies that are currently under investigation and will be discussed here., Competing Interests: Competing interests: The authors alone are responsible for the content and writing of this article. MM consults for MeiraGTx Ltd and TG is MeiraGTx Ltd staff., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

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., Competing Interests: Competing interests: MM consults for MeiraGTx, Stargazer Pharmaceuticals, Janssen Pharmaceuticals, 2C Tech, Acucela and Roche., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

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., Competing Interests: Competing interests: The authors alone are responsible for the content and writing of this article. MM consults for MeiraGTx Ltd., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

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., Competing Interests: Competing interests: The authors alone are responsible for the content and writing of this article. MM and MG consult for MeiraGTx Ltd., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

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., Competing Interests: Competing interests: The authors alone are responsible for the content and writing of this article. MM consults for MeiraGTx., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Aim: To describe the ophthalmologic findings on the largest cohort of patients with sialidosis type I due to deficiency of the lysosomal sialidase, neuraminidase 1 (NEU1) and to introduce a quantitative neuroretinal image analysis approach to the associated 'macular cherry-red spot'., Methods: Seven patients with sialidosis type I (mutations in NEU1 ) and one with galactosialidosis (mutations in CTSA ) were included. All patients underwent detailed ophthalmological examinations. The reflectivity of macular optical coherence tomography (OCT) was measured using greyscale analysis (Fiji) and compared with age-matched healthy volunteers. Four patients were evaluated over a time of 1.5+0.5 years., Results: The mean age of the patients at their first visit was 27.5+9.8 years. All patients had a macular cherry-red spot, clear corneas and visually non-significant lenticular opacities. The mean visual acuity was LogMar 0.4 (20/50)+0.4 (20/20 to 20/125). Six patients had good visual function. Optic atrophy was present in two individuals with reduced acuity. A significant increase in macular reflectivity was present in all patients compared to age-matched controls (p<0.0001)., Conclusion: Most of our patients (75%) have preserved visual acuity, even in adulthood. The presence of optic atrophy is associated with poor visual acuity. Increased macular reflectivity by OCT greyscale measurements is noted in all patients, although the underlying biological basis is unknown. These findings complement the current methods for examining and monitoring disease progression, especially in patients for whom visualisation of the cherry-red spot is not entirely clear., Trial Registration Number: NCT00029965., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)