Night Blindness Research Articles

Revealing the Therapeutic Uses of Garlic (Allium sativum) and Its Potential for Drug Discovery.

Background Garlic is a common bulb vegetable that is used to flavor and flavor food. The plant contains biologically active components that contribute to its pharmacological properties. This paper attempts to examine the therapeutic uses and potential role in the drug development of garlic for various human diseases. Methods To obtain crucial data and scientific knowledge about the therapeutic uses of garlic, systematic literature searches were conducted using key terms on well-known indexed platforms such as PubMed, Scopus, Web of Science, Medline, Embase, and popular search engines. Results Garlic, which is utilized as a spice and flavoring ingredient, is found to have fundamental nutritional components. Carbohydrates, protein, fat, minerals, water, and vitamins are all found in abundance in this plant. The plant also has a high medicinal value and is used to cure a variety of human diseases. It has anti-inflammatory, rheumatological, ulcer inhibiting, anticholinergic, analgesic, antimicrobial, antistress, antidiabetes, anticancer, liver protection, anthelmintics, antioxidants, antifungal, and wound healing properties, as well as properties that help with asthma, arthritis, chronic fever, tuberculosis, runny nose, malaria, leprosy, skin discoloration, and itching, indigestion, colic, enlarged spleen, hemorrhoids, fistula, bone fracture, gout, urinary tract disease, diabetes, kidney stones, anemia, jaundice, epilepsy, cataract, and night blindness. Conclusions The nutritional content of the plant is significant, and it has incredible therapeutic potential. The findings of this study are needed to investigate the therapeutic potential, as it may be a promising option for drug development.

A Combined Approach of Syntonic Phototherapy along with Vision Therapy in Treatment of Rod-Cone Dystrophy: A Ray of Hope - Case Series Report

Background: Rod-Cone Dystrophies (RCDs) are characterized by the dominant clinical features of rods manifestation predominantly over the cones such as night blindness and peripheral vision worsening that leads to restricted activities of daily living. There are no medical or surgical treatments available for this disease. A combined approach of syntonic phototherapy along with the vision therapy may be a viable treatment option for the improvement in visual efficiency skills and visual function of RCD patients. Case Reports: Case 1: A female, aged 47 years old, diagnosed with severe RCD and complained of poor sight and difficulty in seeing at night in both eyes along with progressive diminution of vision for the past ten years. Case 2: A boy, 11 years of age, diagnosed with severe RCD and presented with major complaints of progressive vision loss, photophobia and falling short in school performance. Both patients were recommended for a combined treatment approach of syntonic phototherapy combined with vision therapy to be completed in our centre. Conclusion: These two patients showed significant improvement in visual acuity, oculomotor motility and visual field. Further research is recommended to enrich our understanding on the use of syntonic phototherapy along with vision therapy in managing patients with RCD which otherwise lacks in specific medical or surgical treatment.

The necessity for Zambia's vitamin A sugar fortification requirement

Zambia faces a serious vitamin A deficiency (VAD) that affects most infants and expectant mothers, leading to night blindness, maternal deaths, and more. One of the efforts to address this is by permitting only the manufacture, sale, or import of household consumption sugar which is fortified with vitamin A - which is seen as a disguised restriction on international trade. Through a desk-top research study, the article examines the question, as to what extent Zambia's fortification requirement complies with the necessity principle in the Technical Barrier to Trade Annex to the Southern African Development Community Protocol on Trade (TBT Annex) and Article 2(2) of the World Trade Organization's Agreement on Technical Barriers to Trade (TBT Agreement). The research finds that the measure is a technical regulation with a legitimate objective to protect the health and lives of a target VAD Zambian population. Further, it is applied to both domestic and like foreign products; therefore, it is neither discriminatory nor directly linked to the lack of competitive opportunities for like foreign products. Even if fortified maize meal could be opted for instead of sugar, it cannot achieve the equivalent contribution in dealing with the VAD problem because of challenges, such as, the uncertainty in regulatory regime, and its irregular consumption pattern. Consequently, the sugar fortification requirement is not more trade restrictive than necessary under the TBT Annex and Article 2(2) of the TBT Agreement.

Gyrate Atrophy of the Choroid and Retina: A Review.

Gyrate atrophy (GA) of the choroid and retina is a rare autosomal recessive genetic condition characterized by elevation of the plasma level of the amino acid ornithine due to deficiency of the enzyme ornithine ketoacid aminotransferase. Accumulation of ornithine occurs in various body tissues but leads primarily to characteristic ophthalmic manifestations including myopia, cataract, progressive chorioretinal atrophy, and macular changes. Patients usually present with night blindness that starts in the first decade of life followed by visual field constriction and eventually diminution of the central visual acuity and blindness. The condition has been reported worldwide and its differential diagnosis is broad and includes choroideremia and retinitis pigmentosa. Treatment currently depends on life-long dietary modifications including restriction of the amino acid arginine in diet. This article describes in detail the pathogenesis, clinical features, multimodal imaging findings, and treatment options for GA of the choroid and retina and its complications.

Laurence-Moon-Bardet-Biedl syndrome

Lawrence-Moon-Bardet-Biedl syndrome is a rare autosomal recessive genetic disorder, which may result in a number of multiorgan abnormalities, including impaired brain function, eye diseases, kidney and limbs’ dysfunction. The main symptoms of this syndrome include retinal degeneration, polydactyly, obesity, hypogonadism, congenital kidney abnormalities and mental retardation. However, Lawrence-­Moon­-Barde­-Biedl syndrome may also present with other secondary abnormalities, including ataxia, diabetes insipidus, and dental abnormalities. Clinical changes of the eyes include retinitis pigmentosa, low visual acuity, and vision loss, often due to photoreceptor disorders in the retinal tissue with macular degeneration, leading to night blindness and then, in most cases, can cause complete blindness. In patients with an archetypal manifestation of Lawrence­-Moon­-Barde-­Biedl syndrome, abdominal obesity is common, even if the birth weight is usually normal. In addition, this group of patients has type 2 diabetes mellitus. A distinctive feature of this syndrome is postaxial polydactyly. Hypogonadism, which is a common sign of the disease, as usual can be diagnosed at early age in men in a form of micropenis and testicular hypoplasia).The paper presents clinicalcase of Lawrence­-Moon­-Barde-­Bidle syndrome in a thirteen-year-old boy who referred to endocrinologist with complaints of excessivegain of body weight, memoryloss, visual impairment, difficulties in school, delayedsexual development. Ad ditional investigations enabled to establish the diagnosis of Laurence­-Moon­-Bardet­-Biedl syndrome.

Laurence Moon Bardet Biedl Syndrome with Atypical Syndromic Retinitis Pigmentosa-A Rare Case Report

Laurence Moon Bardet Biedl syndrome is a rare autosomal recessive condition listed in the NORD (National Organisation for Rare Disorders) with only less than 15 cases reported all over India, affects children born to consanguineous parents. Early onset retinal dystrophy, obesity, limb abnormalities, mental retardation, hypogonadism, and renal illness being a few symptoms. Here is a case of 19-year-old male with this rare genetic disorder who presented with complaints of night blindness and defective vision since 2 years. On ocular examination both eye fundus showed atypical retinitis pigmentosa. On systemic examination patient had central obesity, polydactyly, mental retardation, hypogonadism, speech disorder, developmental delay and ataxia.

Genetic Analysis of Consanguineous Pakistani Families with Congenital Stationary Night Blindness

Introduction: Congenital stationary night blindness (CSNB) is a rare, largely nonprogressive, inherited retinal disorder that can be clinically classified on the basis of fundus and electroretinogram abnormalities. Methods: We analyzed four large consanguineous families from the Southern Punjab region of Pakistan including multiple individuals affected with CSNB. Exome sequencing was performed in probands of all four families; Sanger sequencing was performed in additional members to test co-segregation of the variants identified. Results: We identified two novel and likely pathogenic variants in two pedigrees, namely, NM_002905.4:c.668A>C (p.Gln223Pro) in RDH5 and NM_022567.2:c.908del (p.Gly303ValfsTer45) in NYX. In the two other families, the variants NM_002905.4:c.319G>C (p.Gly107Arg) in RDH5 and NM_000541.5:c.874C>T (p.Arg292Ter) in SAG were identified. These latter mutations have been reported previously, but not in the Pakistani population. Conclusions: Our findings expand the mutational spectrum of CSNB, in particular within the population of Southern Punjab.

Ocular Characteristics of Patients with Leber Congenital Amaurosis 6 Caused by Pathogenic RPGRIP1 Gene Variation in a Chinese Cohort.

Purpose To delineate the clinical and genetic characteristics of Chinese patients with RPGRIP1-associated Leber congenital amaurosis 6 (LCA6). Methods After screening 352 unrelated families with clinically diagnosed RP, five LCA6 patients with RPGRIP1 variations from unrelated Chinese families were identified. Full ophthalmology examinations, including decimal best-corrected visual acuity (BCVA), fundus photography, fundus autofluorescence imaging, spectral-domain optical coherence tomography (SD-OCT), full-field electroretinography (ffERG), multifocal electroretinography (mfERG), perimetry, and flash visual evoked potential (FVEP), were performed. Target next-generation sequencing (NGS) and Sanger sequencing were performed for the five patients to identify and to validate candidate disease-causing variants. Results Five patients were molecularly diagnosed as the LCA6 associated with RPGRIP1 variation, with typical clinical characteristics including congenital night blindness, nystagmus, and visual defect, at an early age. Interestingly, LCA6 exhibited extensive clinical heterogeneity and the changes in the morphology and function were not completely consistent in the five LCA6 patients. Case 1 showed extensive inferior-nasal retinal atrophy with a corresponding area of hypofluorescence in fundus autofluorescence, and the fundus photograph was nearly normal in cases 2 and 3. The ERG results displayed a moderately reduced rod-system response in cases 1 and 2 and a significant reduced rod-system response in case 3. Both case 4 and case 5 showed mottled pigmentation in fundi and an unrecordable rod and cone-system response in ERG. Moreover, we identified eight compound variants and one homozygous variant in the five patients with RPGRIP1. Conclusions This is the largest report focused on the clinical electrophysiological features of patients with associated LCA6 caused by the variation in the RPGRIP1 gene in the Chinese population with an enriched phenotypic and genotypic background of LCA6 to improve future gene therapies.

Acquired night blindness due to rod dysfunction after long-term hemodialysis.

To report the clinical findings in 6 patients who developed night blindness after long-term hemodialysis. Retrospective case series. The medical charts of the 6 patients were examined. The fundus photographs, spectral-domain optical coherence tomographic (SD-OCT) images, full-field ERGs, and blood chemistry panels were analyzed. The mean age of the 6 patients (4 men) at the time of diagnosis was 69.1 ± 5.9years. The mean duration of the hemodialysis was 21.8 ± 13.4years (7-41years). The visual acuity of the patients was preserved at 20/30 or better except in 1 eye. Ophthalmoscopy showed white flecks that were scattered over the midperipheral retina in all the eyes. SD-OCT showed mild macular degeneration in 5 eyes. The scotopic ERGs elicited by dim flashes were absent, and those elicited by bright flashes had negative waveforms. The photopic ERGs were relatively well preserved. These data indicated a rod-specific dysfunction that may account for the night blindness. The plasma concentration of vitamin A was within the normal range in 4 of the patients and slightly lower than the normal limit in 1 of the patients. Administration of vitamin A was performed for 1 patient, and the symptom of night blindness and scotopic ERGs were improved 3months later. Long-term hemodialysis can be associated with the night blindness that may be caused by vitamin A deficiency, even though the plasma concentration of vitamin A in these patients was within the normal range.

Fenretinide inhibits vitamin A formation from β-carotene and regulates carotenoid levels in mice

N-[4-hydroxyphenyl]retinamide, commonly known as fenretinide, a synthetic retinoid with pleiotropic benefits for human health, is currently utilized in clinical trials for cancer, cystic fibrosis, and COVID-19. However, fenretinide reduces plasma vitamin A levels by interacting with retinol-binding protein 4 (RBP4), which often results in reversible night blindness in patients. Cell culture and in vitro studies show that fenretinide binds and inhibits the activity of β-carotene oxygenase 1 (BCO1), the enzyme responsible for endogenous vitamin A formation. Whether fenretinide inhibits vitamin A synthesis in mammals, however, remains unknown. The goal of this study was to determine if the inhibition of BCO1 by fenretinide affects vitamin A formation in mice fed β-carotene. Our results show that wild-type mice treated with fenretinide for ten days had a reduction in tissue vitamin A stores accompanied by a two-fold increase in β-carotene in plasma (P < 0.01) and several tissues. These effects persisted in RBP4-deficient mice and were independent of changes in intestinal β-carotene absorption, suggesting that fenretinide inhibits vitamin A synthesis in mice. Using Bco1−/− and Bco2−/− mice we also show that fenretinide regulates intestinal carotenoid and vitamin E uptake by activating vitamin A signaling during short-term vitamin A deficiency. This study provides a deeper understanding of the impact of fenretinide on vitamin A, carotenoid, and vitamin E homeostasis, which is crucial for the pharmacological utilization of this retinoid.

Genotype and Ocular Phenotype in Sixteen Chinese Patients with Bietti Corneoretinal Crystalline Dystrophy

ABSTRACTObjectiveTo investigate CYP4V2 gene variants and ocular clinical characteristics of Bietti corneoretinal crystalline dystrophy in China so as to provide more references for genotype and phenotype of BCD.MethodsSixteen Chinese probands were recruited in Beijing Tongren Hospital in a retrospective study. All patients underwent CYP4V2 gene detection and ophthalmic clinical examinations.ResultsCYP4V2 gene variants were detected in all patients. Eight variants were identified, and the most common one was c.802–8_810del17bpinsGC. Onset age of BCD was from 12 to 44 years, and the first symptoms mostly were decreased visual acuity or night blindness. Corneal crystalline depositions were observed in all patients and were found not only in epithelium and superficial stroma near the limbus but also in corneal endothelium. OCT showed atrophy of RPE in all patients, outer retinal tubulation in ten patients, macular edema in four patients, macular hole in three patients with one accompanied with retinal detachment, and choroidal neovascularization in one patient.ConclusionCYP4V2 gene variants were detected in all patients consistent with the genetic locus homogeneity of BCD, and c.802–8_810del17bpinsGC was the most common mutation. Corneal crystalline depositions were observed in all patients, which may be features of BCD and helpful for the diagnosis of BCD patients, especially those in the advanced stage without typical fundus crystalline depositions or without gene detection. However, considerable phenotypic variability was detected. Corneal crystalline deposits were observed not only in epithelium and superficial stroma but also in endothelium, which has not been reported before. This may provide further evidence for the variable phenotypic expression between affected individuals.

A large animal model of RDH5-associated retinopathy recapitulates important features of the human phenotype.

Pathogenic variants in retinol dehydrogenase 5 (RDH5) attenuate supply of 11-cis-retinal to photoreceptors leading to a range of clinical phenotypes including night blindness because of markedly slowed rod dark adaptation and in some patients, macular atrophy. Current animal models (such as Rdh5-/- mice) fail to recapitulate the functional or degenerative phenotype. Addressing this need for a relevant animal model we present a new domestic cat model with a loss-of-function missense mutation in RDH5 (c.542G > T; p.Gly181Val). As with patients, affected cats have a marked delay in recovery of dark adaptation. In addition, the cats develop a degeneration of the area centralis (equivalent to the human macula). This recapitulates the development of macular atrophy that is reported in a subset of patients with RDH5 mutations and is shown in this paper in seven patients with biallelic RDH5 mutations. There is notable variability in the age at onset of the area centralis changes in the cat, with most developing changes as juveniles but some not showing changes over the first few years of age. There is similar variability in development of macular atrophy in patients and while age is a risk factor, it is hypothesized that genetic modifying loci influence disease severity, and we suspect the same is true in the cat model. This novel cat model provides opportunities to improve molecular understanding of macular atrophy and test therapeutic interventions for RDH5-associated retinopathies.

Retinitis Pigmentosa

Retinitis pigmentosa (RP) is defined as a spectrum of hereditary disorders affecting the photoreceptors and retinal pigment epithelium, leading to progressive peripheral visual loss and night blindness. Retinitis pigmentosa is a leading cause of blindness worldwide and currently, many therapeutic challenges stand in the way of an approved therapy to stop degeneration and restore vision. pigmentosa, its underlying pathophysiology and the diagnostic steps taken by clinicians to recognise RP as well as the management of these patients.

Development and Validation of a Liquid Chromatography Mass Spectrometry Method for Simultaneous Measurement of 25-OH D3, epi-25-OH D3, 25-OH D2, Vitamin A, α-Tocopherol, and γ-Tocopherol

Abstract Background Circulatory fat-soluble vitamin levels are commonly measured to identify deficiencies that may lead to rickets, osteomalacia, night blindness, and reversible motor and sensory neuropathies. We developed and validated a rapid and robust LC-MS/MS method that simultaneously measures 25-OH D3, epi-25-OH D3, 25-OH D2, vitamin A, α-tocopherol, and γ-tocopherol for clinical use. Method 100 µL of serum was mixed with isotope-labeled internal standard and extracted using a 96-well supported-liquid extraction plate with 1.5 mL of hexanes/isopropanol (90/10) (v/v). Dried eluate was reconstituted with 100 µL of methanol/water (90/10) (v/v) and analyzed by LC-MS/MS with a 10-minute gradient. Accuracy was assessed using NIST Standard Reference Materials SRM972a and SRM968f, patient comparison analysis with a LC-MS/MS method at a reference lab, and spike-recovery studies using patient sera and vitamin D-depleted serum. Analytical measurement range (AMR) was determined by spiking 6 analytes into vitamin D-depleted serum to give 7 specimens at varying concentrations. The lower limit of the measuring interval (LLMI) was assessed using 6 pooled specimens with varying low concentrations of each analyte over 20 days. Precision (repeatability and reproducibility) was assessed using quality control materials. Interference studies were performed using pooled patient specimens spiked with varying concentrations of hemoglobin, bilirubin, or intralipid. Matrix effect was assessed by post-column infusion and by matrix dilution with saline. Results The method was linear covering physiological concentrations with r2 &amp;gt; 0.99. Repeatability and reproducibility were &amp;lt;15% CV at all QC levels. LLMI for 25-OH D3, epi-25-OH D3, 25-OH D2, vitamin A, α-tocopherol, and γ-tocopherol were 4 ng/mL (15% CV), 4 ng/mL (15% CV), 4 ng/mL (18% CV), 1 µg/dL (20% CV), 0.2 µg/mL (20% CV), and 0.2 µg/mL (8% CV). Recoveries for NIST Standard Reference Materials were between 92 - 111% and between 81 - 122% for spike-recovery studies. Passing-Bablok analyses for vitamin D total, vitamin A, and α-tocopherol demonstrated slopes between 1.04 and 1.11 and r2 between 0.94 and 0.96. Minimal matrix effect was observed. Conclusions We have developed and validated a comprehensive and rapid LC-MS/MS method for the simultaneous measurement of 25-OH D3, epi-25-OH D3, 25-OH D2, vitamin A, α-tocopherol, and γ-tocopherol for clinical use.

Electrochemical Detection of Chloroquine Using Ion-Selective Electrodes

Ion-selective electrodes have been thoroughly studied over the past three decades and have produced analytical devices for the detection of several important analytes (e.g., K+, Na+, bilirubin, etc.) in complex matrices like blood or urine. Most ion-selective electrodes contain a molecular recognition element (i.e., ionophore) to increase selectivity towards a specific analyte. Chloroquine has been used in antimalarial treatments for over 50 years, however, chloroquine has been connected to the onset of retinopathy. Retinopathy is an ophthalmic disease which can lead to partial blindness (i.e., peripheral blindness or night blindness) or, in extreme cases, complete blindness. Currently, expensive benchtop equipment such as HPLC and UV-Vis spectroscopy are used to measure chloroquine levels. Interestingly, although chloroquine is a highly lipophilic molecule, there are no reports of potentiometric sensors being applied towards the detection of chloroquine. This research describes the development of ion-selective electrodes doped with ionophores for the rapid quantification of chloroquine. The investigated ionophores have been previously studied with respect to their binding to chloroquine and show strong indications that they can provide the selectivity required to measure chloroquine in diverse biological fluids. Each chloroquine ion-selective electrode was analyzed for its selectivity, linear detection range, stability, and reproducibility.

Molecular Therapy for Choroideremia: Pre-clinical and Clinical Progress to Date.

Choroideremia is an inherited retinal disease characterised by a degeneration of the light-sensing photoreceptors, supporting retinal pigment epithelium and underlying choroid. Patients present with the same symptoms as those with classic rod-cone dystrophy: (1) night blindness early in life; (2) progressive peripheral visual field loss, and (3) central vision decline with a slow progression to legal blindness. Choroideremia is monogenic and caused by mutations in CHM. Eight clinical trials (three phase 1/2, four phase 2, and one phase 3) have started (four of which are already finished) to evaluate the therapeutic efficacy of gene supplementation mediated by subretinal delivery of an adeno-associated virus serotype 2 (AAV2/2) vector expressing CHM. Furthermore, one phase 1 clinical trial has been initiated to evaluate the efficiency of a novel AAV variant to deliver CHM to the outer retina following intravitreal delivery. Lastly, a non-viral-mediated CHM replacement strategy is currently under development, which could lead to a future clinical trial. Here, we summarise the rationale behind these various studies, as well as any results published to date. The diversity of these trials currently places choroideremia at the forefront of the retinal gene therapy field. As a consequence, the trial outcomes, regardless of the results, have the potential to change the landscape of gene supplementation for inherited retinal diseases.

Retinitis pigmentosa and molar tooth sign caused by novel AHI1 compound heterozygote pathogenic variants

BackgroundJoubert syndrome (JS) is a group of rare congenital disorders characterized by cerebellar vermis dysplasia, developmental delay, and retina dysfunctions. Herein, we reported a Chinese patient carrying a new variant in the AHI1 gene with mild JS, and the 3D structure of the affected Jouberin protein was also predicted.Case presentationThe patient was a 31-year-old male, who presented difficulty at finding toys at the age of 2 years, night blindness from age of 5 years, intention tremor and walking imbalance from 29 years of age. Tubular visual field and retina pigmentation were observed on ophthalmology examinations, as well as molar tooth sign on brain magnetic resonance imaging (MRI). Whole exome sequence revealed two compound heterozygous variants at c.2105C>T (p.T702M) and c.1330A>T (p.I444F) in AHI1 gene. The latter one was a novel mutation. The 3D protein structure was predicted using I-TASSER and PyMOL, showing structural changes from functional β-sheet and α-helix to non-functional D-loop, respectively.ConclusionsMild JS due to novel variants at T702M and I444F in the AHI1 gene was reported. The 3D-structural changes in Jouberin protein might underlie the pathogenesis of JS.

Biofortification of Cereals and Pulses Using New Breeding Techniques: Current and Future Perspectives.

Cereals and pulses are consumed as a staple food in low-income countries for the fulfillment of daily dietary requirements and as a source of micronutrients. However, they are failing to offer balanced nutrition due to deficiencies of some essential compounds, macronutrients, and micronutrients, i.e., cereals are deficient in iron, zinc, some essential amino acids, and quality proteins. Meanwhile, the pulses are rich in anti-nutrient compounds that restrict the bioavailability of micronutrients. As a result, the population is suffering from malnutrition and resultantly different diseases, i.e., anemia, beriberi, pellagra, night blindness, rickets, and scurvy are common in the society. These facts highlight the need for the biofortification of cereals and pulses for the provision of balanced diets to masses and reduction of malnutrition. Biofortification of crops may be achieved through conventional approaches or new breeding techniques (NBTs). Conventional approaches for biofortification cover mineral fertilization through foliar or soil application, microbe-mediated enhanced uptake of nutrients, and conventional crossing of plants to obtain the desired combination of genes for balanced nutrient uptake and bioavailability. Whereas, NBTs rely on gene silencing, gene editing, overexpression, and gene transfer from other species for the acquisition of balanced nutritional profiles in mutant plants. Thus, we have highlighted the significance of conventional and NBTs for the biofortification of cereals and pulses. Current and future perspectives and opportunities are also discussed. Further, the regulatory aspects of newly developed biofortified transgenic and/or non-transgenic crop varieties via NBTs are also presented.

Metabolic rescue of cone photoreceptors in retinitis pigmentosa.

Retinitis pigmentosa (RP) encompasses a group of inherited retinal dystrophies characterized by the primary degeneration of rod and cone photoreceptors. It is a leading cause of visual disability, with an incidence of ~1 in 7000 persons. Although most RP is nonsyndromic, 20%–30% of patients with RP also have an associated nonocular condition. The gene mutations responsible for RP occur overwhelmingly in rod photoreceptors. Visual loss frequently begins with night blindness in adolescence, followed by concentric visual field loss, reflecting the principal dysfunction of rod photoreceptors. Although the visual disability from rod dysfunction is significant, it is the subsequent loss of central vision later in life due to cone degeneration that is catastrophic. Until recently, the reason for cone dysfunction in RP was unknown. However, it is now recognized that cones degenerate, losing outer segment (OS) synthesis and inner segment (IS) disassembly because of glucose starvation following rod demise. Rod OS phagocytosis by the apical microvilli of retinal pigment epithelium is necessary to transport glucose from the choriocapillaris to the subretinal space. Although cones lose OS with the onset of rod degeneration in RP, regardless of the gene mutation in rods, cone nuclei remain viable for years (i.e. enter cone dormancy) so that therapies aimed at reversing glucose starvation can prevent and/or recover cone function and central vision.

Retinal Gene Therapy for Usher Syndrome: Current Developments, Challenges, and Perspectives.

Usher syndrome (USH) represents a group of genetically heterogenous autosomal recessive disorders, characterized by combined vision and sensorineural hearing loss, and in some cases vestibular dysfunction.1–3 It primarily affects the light-sensitive photoreceptor cells in the retina and the auditory hair cells in the cochlea. Vision loss in all cases is progressive, and manifests as retinitis pigmentosa (RP), characterized by the gradual degeneration of the photoreceptor cells.4 Peripheral rod function is lost first, leading to night blindness and constricted visual fields, followed by the death of cones and severe visual impairment. There are currently no drugs or biological therapies proven to be effective in treating USH syndrome. Cochlear implantation, which bypasses the damaged hair cells and stimulates the primary auditory neurons directly, is an effective approach to alleviate the hearing impairment in patients. However, there is no remedy for the progressive loss of the photoreceptor neurons in the retina, and thus a critical unmet need exists to develop therapeutic strategies to prevent blindness in USH syndrome. The generation of animal models that faithfully mimic the human USH disorder, the timing of gene therapy interventions, the identification of correct target cells and patient selection are key factors in successfully reaching this goal. USH syndrome was named after Dr Charles Howard Usher, a Scottish ophthalmologist who described 69 patients with the disease in 1914.5 As is commonly the case in medicine, the disease was first described much earlier (1858) in brothers suffering from blindness and deafness by von Grafe6 and was further characterized by his student, Liebreich,7 3 years later in a larger population of patients. From its discovery until recently, USH syndrome and its subgroups were delineated by clinical characteristics.8 Now the disease is recognized by symptomology and classified by genotyping. To date, there are at least 10 causative genes that are associated with USH syndrome, summarized in previous reviews.1,2,9 In general, based on its diverse clinical symptoms, particularly the onset and severity of the sensorineural hearing impairment and the presence of vestibular dysfunction, USH syndrome is grouped into 3 clinical subtypes. Type I disease is associated with severe-to-profound prelingual hearing loss, vestibular abnormalities and prepubescent onset of RP symptoms.10,11 USH1 results from mutations in MYO7A (USH1B), HARMONIN (USH1C), CDH23 (USH1D), PCDH15 (USH1F), SANS (USH1G), and CIB2 (USH1J). Patients with type II disease display moderate-to-severe congenital hearing loss without vestibular dysfunction, and account for >50% of all USH cases. Their RP symptoms generally begin in the second decade.12 USH2 is caused by mutations in USH2A (USH2A), ADGRV1 (USH2C), and WHRN (USH2D). Patients with type III disease caused by mutations in CLRN1 (USH3A) gene have postlingual progressive hearing loss, variable vestibular dysfunction, and variable onset of RP that rapidly progresses to legal blindness by the fourth decade of life.13–17 Mutations in the HARS gene (Histidyl-tRNA synthetase) are associated with the ultra-rare form USH3B.18,19 Other genes have been described in cases of atypical USH, including: CEP250 and CEP78, encoding members of the CEP family of centrosome-associated proteins; ESPN, encoding the F-actin cross-linker espin; ARSG, encoding the arylsulfatase G enzyme.20