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Leber congenital amaurosis, caused by mutations in RPE65 and LRAT, is a severe form of inherited retinal degeneration leading to blindness. We aimed to assess replacement of the missing chromophore 11-cis retinal with oral QLT091001 (synthetic 9-cis-retinyl acetate) in these patients. In our open-label, prospective, phase 1b trial, we enrolled patients (aged ≥6 years) with Leber congenital amaurosis and RPE65 or LRAT mutations at McGill University's Montreal Children's Hospital. Patients received 7 days of oral QLT091001 (10–40 mg/m2 per day). We assessed patients at baseline and days 7, 9, 14, and 30, and then 2 months and every 2 months thereafter for up to 2·2 years for safety outcomes and visual function endpoints including Goldmann visual fields (GVF), visual acuity, and functional MRI assessment. We regarded patients as having an improvement in vision if we noted at least a 20% improvement in retinal area on GVF compared with baseline or a visual acuity improvement of five or more letters compared with baseline in two consecutive study visits (or any improvement from no vision at baseline). This study is registered with ClinicalTrials.gov, number NCT01014052. Between December, 2009, and June, 2011, we enrolled and treated 14 patients aged 6–38 years who were followed up until March, 2012. Ten (71%) of 14 patients had an improvement in GVF areas (mean increase in retinal area of 28–683%). Six (43%) patients had an improvement in visual acuity (mean increase of 2–30 letters). Self-reported or parent-reported improvements in activities of daily living supported these findings. After 2 years, 11 (79%) patients had returned to their baseline GVF retinal area and ten (71%) had returned to baseline visual acuity letter values. Thus, three (21%) patients had a sustained GVF response and four (30%) had a sustained visual acuity response. Four patients had functional MRI scans, which correlated with visual response or absence of response to treatment. No serious adverse events occurred, although we noted transient headaches (11 patients), photophobia (11 patients), reduction in serum HDL concentrations (four patients), and increases in serum triglycerides (eight patients) and aspartate aminotransferase concentrations (two patients). Non-invasive oral QLT091001 therapy is well tolerated, and can rapidly improve visual function in some patients with Leber congenital amaurosis and RPE65 and LRAT mutations. QLT, Foundation Fighting Blindness Canada, CIHR, FRSQ, Reseau Vision.

Leber congenital amaurosis (LCA) is the earliest and most severe form of all inherited retinal dystrophies, responsible for congenital blindness. Disease‐associated mutations have been hitherto reported in seven genes. These genes are all expressed preferentially in the photoreceptor cells or the retinal pigment epithelium but they are involved in strikingly different physiologic pathways resulting in an unforeseeable physiopathologic variety. This wide genetic and physiologic heterogeneity that could largely increase in the coming years, hinders the molecular diagnosis in LCA patients. The genotyping is, however, required to establish genetically defined subgroups of patients ready for therapy. Here, we report a comprehensive mutational analysis of the all known genes in 179 unrelated LCA patients, including 52 familial and 127 sporadic (27/127 consanguineous) cases. Mutations were identified in 47.5% patients. GUCY2D appeared to account for most LCA cases of our series (21.2%), followed by CRB1 (10%), RPE65 (6.1%), RPGRIP1 (4.5%), AIPL1 (3.4%), TULP1 (1.7%), and CRX (0.6%). The clinical history of all patients with mutations was carefully revisited to search for phenotype variations. Sound genotype–phenotype correlations were found that allowed us to divide patients into two main groups. The first one includes patients whose symptoms fit the traditional definition of LCA, i.e., congenital or very early cone‐rod dystrophy, while the second group gathers patients affected with severe yet progressive rod‐cone dystrophy. Besides, objective ophthalmologic data allowed us to subdivide each group into two subtypes. Based on these findings, we have drawn decisional flowcharts directing the molecular analysis of LCA genes in a given case. These flowcharts will hopefully lighten the heavy task of genotyping new patients but only if one has access to the most precise clinical history since birth. Hum Mutat 23:306–317, 2004 © 2004 Wiley‐Liss, Inc.

Refractive errors, including myopia, are the most frequent eye disorders worldwide and an increasingly common cause of blindness. This genome-wide association meta-analysis in 160,420 participants and replication in 95,505 participants increased the number of established independent signals from 37 to 161 and showed high genetic correlation between Europeans and Asians (>0.78). Expression experiments and comprehensive in silico analyses identified retinal cell physiology and light processing as prominent mechanisms, and also identified functional contributions to refractive-error development in all cell types of the neurosensory retina, retinal pigment epithelium, vascular endothelium and extracellular matrix. Newly identified genes implicate novel mechanisms such as rod-and-cone bipolar synaptic neurotransmission, anterior-segment morphology and angiogenesis. Thirty-one loci resided in or near regions transcribing small RNAs, thus suggesting a role for post-transcriptional regulation. Our results support the notion that refractive errors are caused by a light-dependent retina-to-sclera signaling cascade and delineate potential pathobiological molecular drivers. Transancestral GWAS meta-analysis in 160,420 individuals identifies 139 loci associated with refractive error, including myopia. Newly identified genes implicate pathways involved in eye growth and light signaling cascades.

Safety and efficacy have been shown in a phase 1 dose-escalation study involving a unilateral subretinal injection of a recombinant adeno-associated virus (AAV) vector containing the RPE65 gene (AAV2-hRPE65v2) in individuals with inherited retinal dystrophy caused by RPE65 mutations. This finding, along with the bilateral nature of the disease and intended use in treatment, prompted us to determine the safety of administration of AAV2-hRPE65v2 to the contralateral eye in patients enrolled in the phase 1 study. In this follow-on phase 1 trial, one dose of AAV2-hRPE65v2 (1·5 × 1011 vector genomes) in a total volume of 300 μL was subretinally injected into the contralateral, previously uninjected, eyes of 11 children and adults (aged 11–46 years at second administration) with inherited retinal dystrophy caused by RPE65 mutations, 1·71–4·58 years after the initial subretinal injection. We assessed safety, immune response, retinal and visual function, functional vision, and activation of the visual cortex from baseline until 3 year follow-up, with observations ongoing. This study is registered with ClinicalTrials.gov, number NCT01208389. No adverse events related to the AAV were reported, and those related to the procedure were mostly mild (dellen formation in three patients and cataracts in two). One patient developed bacterial endophthalmitis and was excluded from analyses. We noted improvements in efficacy outcomes in most patients without significant immunogenicity. Compared with baseline, pooled analysis of ten participants showed improvements in mean mobility and full-field light sensitivity in the injected eye by day 30 that persisted to year 3 (mobility p=0·0003, white light full-field sensitivity p<0·0001), but no significant change was seen in the previously injected eyes over the same time period (mobility p=0·7398, white light full-field sensitivity p=0·6709). Changes in visual acuity from baseline to year 3 were not significant in pooled analysis in the second eyes or the previously injected eyes (p>0·49 for all time-points compared with baseline). To our knowledge, AAV2-hRPE65v2 is the first successful gene therapy administered to the contralateral eye. The results highlight the use of several outcome measures and help to delineate the variables that contribute to maximal benefit from gene augmentation therapy in this disease. Center for Cellular and Molecular Therapeutics at The Children's Hospital of Philadelphia, Spark Therapeutics, US National Institutes of Health, Foundation Fighting Blindness, Institute for Translational Medicine and Therapeutics, Research to Prevent Blindness, Center for Advanced Retinal and Ocular Therapeutics, Mackall Foundation Trust, F M Kirby Foundation, and The Research Foundation—Flanders.

In zebrafish, Müller glia (MG) are a source of retinal stem cells that can replenish damaged retinal neurons and restore vision 1 . In mammals, however, MG do not spontaneously re-enter the cell cycle to generate a population of stem or progenitor cells that differentiate into retinal neurons. Nevertheless, the regenerative machinery may exist in the mammalian retina, as retinal injury can stimulate MG proliferation followed by limited neurogenesis 2 – 7 . Therefore, there is still a fundamental question regarding whether MG-derived regeneration can be exploited to restore vision in mammalian retinas. Gene transfer of β-catenin stimulates MG proliferation in the absence of injury in mouse retinas 8 . Here we report that following gene transfer of β-catenin, cell-cycle-reactivated MG can be reprogrammed to generate rod photoreceptors by subsequent gene transfer of transcription factors essential for rod cell fate specification and determination. MG-derived rods restored visual responses in Gnat1 rd17 Gnat2 cpfl3 double mutant mice, a model of congenital blindness 9 , 10 , throughout the visual pathway from the retina to the primary visual cortex. Together, our results provide evidence of vision restoration after de novo MG-derived genesis of rod photoreceptors in mammalian retinas. Müller glia in mature mouse retina can be stimulated to produce rod cells; this treatment restores visual responses in a model of congenital blindness.

Leber's congenital amaurosis (LCA) is a group of inherited disorders involving retinal degeneration with severe vision loss noted in early infancy. The condition is usually identified through behaviors, including abnormal roving-eye movements (nystagmus). The diagnosis is confirmed by both abnormal electroretinographic responses and pupillary light reflexes. 1 – 4 Most patients with LCA have severe visual impairment throughout childhood; vision deteriorates over time, and patients usually have total blindness by the third or fourth decade of life. 4 There is no treatment for LCA. The LCA2 form of the disease is associated with mutations in RPE65, which encodes a protein requisite for the . . .

A form of Leber's congenital amaurosis is caused by mutant RPE65 , a critical component of the visual cycle. Two early clinical trials to assess subretinal injection of a viral vector containing RPE65 in young adults with advanced retinal degeneration show that this approach is generally safe in the short term, although one group reported an adverse event: macular hole. The authors observed improvement in some measures of visual function. Two early clinical trials to assess subretinal injection of a viral vector containing RPE65 in young adults with advanced retinal degeneration show that this approach is generally safe in the short term, although one group reported an adverse event: macular hole. The authors observed improvement in some measures of visual function. Leber's congenital amaurosis is a term used to describe a group of recessively inherited, severe, infantile-onset rod–cone dystrophies. 1 Mutation of one of several genes, including RPE65 , causes disease that involves impaired vision from birth 2 , 3 and typically progresses to blindness in the third decade of life. There is no effective treatment. RPE65 is expressed in the retinal pigment epithelium and encodes a 65-kD protein that is a key component of the visual cycle, 1 , 4 – 8 a biochemical pathway that regenerates the visual pigment after exposure to light. 9 – 14 A lack of functional RPE65 results in deficiency of 11- cis . . .

Key Points Age-related macular degeneration (AMD) is the leading cause of blindness in elderly individuals in the developed world. It features a progressive deterioration of the central retina. Numerous, sometimes contradictory, pro-inflammatory signals and pathways have been implicated in disease initiation and progression. In the healthy retina, ocular immune-based surveillance has an essential role in maintaining visual homeostasis. As the retina ages and deteriorates, diverse pro-inflammatory agonists induce improper local immune activation. Diverse immune pathways including complement, the inflammasome, Toll-like receptor activation, adaptive immunity and others are implicated in driving retinal damage in AMD. Extraocular immune cell recruitment mediates pathological angiogenesis in neovascular AMD, which is a prevalent condition that is defined by the growth of unwanted, abnormal blood vessels in the normally avascular macular area. Numerous completed and ongoing immune-based clinical trials for AMD have been unanimously unsuccessful. This may be the result of our collective lack of understanding and appreciation of the 'friend–foe' relationship between retinal degeneration and immunity. Immune dysfunction is a recurring theme in the pathogenesis of age-related macular degeneration, which is the leading cause of blindness in aged individuals. Understanding the dual nature of ocular immune pathways in both visual homeostasis and retinal damage could aid the development of immune-based therapeutics for this disease. Age-related macular degeneration (AMD) is a leading cause of blindness in aged individuals. Recent advances have highlighted the essential role of immune processes in the development, progression and treatment of AMD. In this Review we discuss recent discoveries related to the immunological aspects of AMD pathogenesis. We outline the diverse immune cell types, inflammatory activators and pathways that are involved. Finally, we discuss the future of inflammation-directed therapeutics to treat AMD in the growing aged population.

Gene therapy has the potential to reverse disease or prevent further deterioration of vision in patients with incurable inherited retinal degeneration. We therefore did a phase 1 trial to assess the effect of gene therapy on retinal and visual function in children and adults with Leber's congenital amaurosis. We assessed the retinal and visual function in 12 patients (aged 8–44 years) with RPE65-associated Leber's congenital amaurosis given one subretinal injection of adeno-associated virus (AAV) containing a gene encoding a protein needed for the isomerohydrolase activity of the retinal pigment epithelium (AAV2-hRPE65v2) in the worst eye at low (1·5×10 10 vector genomes), medium (4·8×10 10 vector genomes), or high dose (1·5×10 11 vector genomes) for up to 2 years. AAV2-hRPE65v2 was well tolerated and all patients showed sustained improvement in subjective and objective measurements of vision (ie, dark adaptometry, pupillometry, electroretinography, nystagmus, and ambulatory behaviour). Patients had at least a 2 log unit increase in pupillary light responses, and an 8-year-old child had nearly the same level of light sensitivity as that in age-matched normal-sighted individuals. The greatest improvement was noted in children, all of whom gained ambulatory vision. The study is registered with ClinicalTrials.gov, number NCT00516477. The safety, extent, and stability of improvement in vision in all patients support the use of AAV-mediated gene therapy for treatment of inherited retinal diseases, with early intervention resulting in the best potential gain. Center for Cellular and Molecular Therapeutics at the Children's Hospital of Philadelphia, Foundation Fighting Blindness, Telethon, Research to Prevent Blindness, F M Kirby Foundation, Mackall Foundation Trust, Regione Campania Convenzione, European Union, Associazione Italiana Amaurosi Congenita di Leber, Fund for Scientific Research, Fund for Research in Ophthalmology, and National Center for Research Resources.

Adeno-associated virus (AAV)–based gene therapies aimed at curing inherited retinal diseases to date have typically focused on photoreceptors and retinal pigmented epithelia within the relatively accessible outer retina. However, therapeutic targeting in diseases such as congenital stationary night blindness (CSNB) that involve defects in ON-bipolar cells (ON-BCs) within the midretina has been challenged by the relative inaccessibility of the target cell in intact retinas, the limited transduction efficiency of these cells by existing AAV serotypes, poor availability of established ON-BC–specific promoters, and the absence of appropriate patient-relevant large animal models. Here, we demonstrate safe and effective ON-BC targeting by AAV gene therapy in a recently characterized naturally occurring canine model of CSNB: leucine-rich repeat, immunoglobulin-like and transmembrane domain 3 (LRIT3)–CSNB. To effectively target ON-BCs, AAV capsid variants with ON-BC tropism and ON-BC–specific modified GRM6 promoters were adopted to ensure cell-specific transgene expression. Subretinal injection of one vector, AAVK9#4-shGRM6-cLRIT3-WPRE, significantly recovered rod-derived b-wave in all treated eyes (six of six) of adult dogs injected at 1 to 3 y of age. The robust therapeutic effect was evident 7 wk postinjection and sustained for at least 1 y in all treated eyes. Scotopic vision was significantly improved in treated eyes based on visually guided obstacle course navigation. Restoration of LRIT3 signals was confirmed by immunohistochemistry. Thus, we report ON-BC functional rescue in a large animal model using an AAV capsid variant and modified promoter construct optimized for ON-BC specificity, thereby establishing both proof of concept and a translational platform for treatment of CSNB in patients with defects in photoreceptor-to-bipolar signaling.