First in man study of intravitreal tripeptidyl peptidase 1 for CLN2 retinopathy.

BACKGROUND/OBJECTIVES: CLN2 Batten Disease is a fatal neurodegenerative condition of childhood associated with retinal dystrophy and blindness. Intracerebroventricular infusion of rhTPP1 greatly slows the rate of neurodegenerative decline but not retinopathy. Intravitreal rhTPP1 is known to slow retinal degeneration in a canine model of CLN2. We report a first-in-man controlled clinical trial of intravitreal rhTPP1 for CLN2 associated retinal dystrophy. SUBJECTS/METHODS: 8 children aged 5-9 with CLN2 Batten Disease were prospectively enroled. Severely affected patients were preferentially selected, provided that vision was better than no perception of light. Children underwent 8 weekly intravitreal injections of rhTPP1 (0.2 mg in 0.05 ml) into the right eye for 12-18 months. The left eye was untreated and acts as a paired control. The primary outcome was safety based on the clinical detection of complications. A secondary outcome was paracentral macular volume (PMV) measured by spectral domain OCT. Linear regression/paired t tests were used to compare rates of decline. RESULTS: No severe adverse reactions (uveitis, raised IOP, media opacity) occurred. The mean baseline PMV was 1.28 mm3(right), 1.27 mm3(left). 3 of the youngest patients exhibited bilateral progressive retinal thinning (p < 0.05), whereas retinal volume was stable in the remaining 5 patients. In the 3 patients undergoing retinal degeneration, the rate of PMV loss was slower in the treated vs. untreated eye (p = 0.000042, p = 0.0011, p = 0.00022). CONCLUSIONS: Intravitreal rhTPP1 appears to be a safe and effective treatment for CLN2 related retinopathy however commencement of treatment early in the course of disease is more likely to be efficacious.

Large Benefit from Simple Things: High-Dose Vitamin A Improves RBP4-Related Retinal Dystrophy.

Inherited retinal diseases (IRD) are a group of heterogeneous disorders, most of which lead to blindness with limited therapeutic options. Pathogenic variants in RBP4, coding for a major blood carrier of retinol, retinol-binding protein 4, are responsible for a peculiar form of IRD. The aim of this study was to investigate if retinal function of an RBP4-related IRD patient can be improved by retinol administration. Our patient presented a peculiar white-dot retinopathy, reminiscent of vitamin A deficient retinopathy. Using a customized next generation sequencing (NGS) IRD panel we discovered a novel loss-of-function homozygous pathogenic variant in RBP4: c.255G >A, p.(Trp85*). Western blotting revealed the absence of RBP4 protein in the patient's serum. Blood retinol levels were undetectable. The patient was put on a high-dose oral retinol regimen (50,000 UI twice a week). Subjective symptoms and retinal function markedly and sustainably improved at 5-months and 1-year follow-up. Here we show that this novel IRD case can be treated by oral retinol administration.

Durability of Voretigene Neparvovec for Biallelic RPE65-Mediated Inherited Retinal Disease: Phase 3 Results at 3 and 4 Years.

PURPOSE: To determine whether functional vision and visual function improvements after voretigene neparvovec (VN; Luxturna [Spark Therapeutics, Inc]) administration in patients with biallelic RPE65 mutation-associated inherited retinal disease are maintained at 3 to 4 years and to review safety outcomes. DESIGN: Open-label, randomized, controlled phase 3 trial. PARTICIPANTS: Thirty-one individuals were enrolled and randomized 2:1 to intervention (n = 21) or control (n = 10). One participant from each group withdrew before, or at, randomization. METHODS: Patients in the original intervention (OI) group received bilateral subretinal VN injections. Delayed intervention (DI) patients served as control participants for 1 year then received VN. MAIN OUTCOME MEASURES: Change from injection baseline in bilateral performance on the multiluminance mobility test (MLMT), a measure of ambulatory navigation, and change from injection baseline in full-field light sensitivity threshold white light, visual field (VF), and visual acuity (VA). RESULTS: Mean bilateral MLMT change scores at year 4 for OI patients and year 3 for DI patients were 1.7 and 2.4, respectively, with 71% of patients with a year 3 visit able to pass MLMT at the lowest light level. Mean change in full-field light sensitivity threshold white light, averaged over both eyes at year 4 for OI patients and year 3 for DI patients, was -1.90 log10(cd.s/m2) and -2.91 log10(cd.s/m2), respectively. Mean change in Goldmann kinetic VF III4e sum total degrees, averaged across both eyes, was 197.7 at year 4 for OI patients and 157.9 at year 3 for DI patients. Mean change in VA (Holladay scale), averaged across both eyes, was -0.003 logarithm of the minimum angle of resolution (logMAR) at year 4 for OI patients and -0.06 logMAR at year 3 for DI patients. One OI patient experienced retinal detachment at approximately year 4 that impacted VA for the OI group. No product-related serious adverse events (AEs) occurred, nor did any deleterious immune responses. CONCLUSIONS: Improvements in ambulatory navigation, light sensitivity, and VF were consistent in both intervention groups. Overall, improvements were maintained up to 3 to 4 years, with ongoing observation. The safety profile of VN was consistent with vitrectomy and the subretinal injection procedure and was similar between intervention groups, with no product-related serious AEs reported.

Anti-VEGF and Retinal Dystrophies.

The therapeutic approach based on anti-vascular endothelial growth factor (anti-VEGF) molecules can be used to treat two important complications of retinal dystrophies: choroidal neovascularization and macular edema. The macular involvement in retinal dystrophies can lead to further visual deterioration in patients at a young age and already affected by functional limitations. The study reports the effect of anti-VEGF treatment in several subforms of retinal dystrophies, critically discussing advantages and limitations.

Emerging Drug Therapies for Inherited Retinal Dystrophies.

Worldwide, 1 in 2000 people suffer from inherited retinal dystrophies (IRD). Individuals with IRD typically present with progressive vision loss that ultimately results in blindness. Unfortunately, effective treatment options are not widely available due to the genetic and clinical heterogeneity of these diseases. There are multiple gene, cell, and drug-based therapies in various phases of clinical trials for IRD. This mini-review documents current progress made in drug-based clinical trials for treating IRD.

Efficacy of topical brinzolamide in children with retinal dystrophies.

Background: Inherited retinal dystrophies are a leading cause of irreversible blindness in children in the United States. Topical carbonic anhydrase inhibitors have improved central vision and cystoid macular edema in patients with retinal dystrophies, but few studies have assessed their efficacy in children. Materials and Methods: A retrospective chart review was performed with Institutional Review Board approval to identify pediatric patients with inherited retinal dystrophies who received topical brinzolamide at a single university center between 2008 and 2015. Serial visual acuity and central macular thicknesses were compared to assess the efficacy of brinzolamide. Results: Seven subjects were identified who met the inclusion criteria. Four had juvenile X-linked retinoschisis, two had retinitis pigmentosa, and one had Leber congenital amaurosis. All were prescribed brinzolamide thrice daily; however, one patient was completely non-compliant. Four of the six treated patients exhibited a mild decrease in central macular thickness in both eyes during the study with all six treated patients having significantly improved vision at the first endpoint, 33.2 ± 8.2 months after treatment initiation. For treated patients, average visual acuity (LogMAR) ± standard error of the mean improved from 0.5 ± 0.04 pre-treatment to 0.3 ± 0.1 at the second endpoint, 50.2 ± 7.3 months after treatment initiation. Conclusions: Mild anatomic improvement of macular cysts was seen in pediatric patients using brinzolamide. Visual acuity improvement occurred even without significant reduction in macular cysts. Further studies are needed to determine whether the beneficial effects of carbonic anhydrase inhibitors are sustained in children with inherited retinal degenerations.

Paradoxical response to carbonic anhydrase inhibitors in patients with intraretinal cystoid spaces.

Background: Intraretinal cystoid spaces (IRCS) are fluid-filled spaces seen in some retinal dystrophies and often treated with carbonic anhydrase inhibitors. The purpose of this study is to report an unexpected bilateral improvement in the IRCS after discontinuation of therapy. Material and Methods: We identified from our records 23 patients with retinal dystrophy and IRCS who had been treated with topical and/or oral carbonic anhydrase inhibitors. All subjects had regular follow-up with OCT and previous genetic testing. Results: We identified four (17%) patients who experienced a bilateral and symmetrical paradoxical improvement in IRCS size and visual acuity after discontinuation of carbonic anhydrase inhibitors. Two were mutations in RS1, one in CLN3 and another in NR2E3. All patients were followed for at least three years (range 39-63 months). None had systemic abnormalities. Conclusions: Patients with IRCS may exhibit a paradoxical response after discontinuation of carbonic anhydrase inhibitors. Although the pathophysiology of these phenomena is unclear, stopping treatment may be an option in patients who cease to improve or get worse on treatment.

Anti-VEGF treatment for choroidal neovascularization complicating pattern dystrophy-like deposit associated with pseudoxanthoma elasticum.

PURPOSE: To evaluate the efficacy of intravitreal anti-VEGF injections in choroidal neovascularization (CNV) related to pattern dystrophy-like deposit in pseudoxanthoma elasticum (PXE). METHODS: One-year prospective, interventional study. Nine eyes were recruited in the ophthalmology departments of San Raffaele University and University of Barcelona. Each patient underwent best corrected visual acuity (BCVA) measurement on ETDRS chart, slit-lamp biomicroscopy, fluorescein angiography (FA), indocyanine green angiography (ICGA), and optical coherence tomography (OCT). The protocol included a first anti-VEGF injection, followed by monthly evaluations with re-treatments based on new funduscopic hemorrhages, fluid on OCT or leakage on FA and/or ICGA. Primary outcome measures were the mean BCVA changes. Secondary outcomes included central macular thickness (CMT) variations and the number of injections needed. RESULTS: At month 12, mean BCVA significantly improved from 20/45 to 20/35 Snellen equivalent, with 3 eyes gaining at least 3 ETDRS lines. Mean CMT decreased from 297 ± 22 to 262 ± 13 µm, after 5.5 ± 4.0 injections. No leakage was observed at the end of follow-up. CONCLUSIONS: Intravitreal anti-VEGF injections represent an effective treatment for CNV related to pattern dystrophy-like deposit in PXE, with an improvement of BCVA and CMT. Mean injection number is in line with other studies performed in CNV secondary to angioid streaks.

Treatment of cystoid macular edema in homozygous twins with glutathione synthetase deficiency and retinal dystrophy.

Monozygotic twins with glutathione synthetase deficiency, progressive retinal dystrophy and cystoid macular edema were followed for foveal changes on optical coherence tomography under different treatment modalities. The purpose of the study is to show the effect of topical dorzolamide in conjunction with systemic acetazolamide in terms of decreasing macular edema in this specific disease. The results showed that systemic acetazolamide alone or in combination with topical dorzolamide decreased CME in both patients for a certain period of time. The result can be temporary sustained after treatment discontinuation. In conclusion, topical dorzolamide, in conjunction with systemic acetazolamide, could reduce cystoid macular edema in GSSD.

Eye Findings on Vigabatrin and Taurine Treatment in Two Patients with Succinic Semialdehyde Dehydrogenase Deficiency.

We describe for the first time two patients with succinic semialdehyde dehydrogenase (SSADH) deficiency, who were found to have abnormal electroretinogram (ERG) examinations at baseline, or 6 months after vigabatrin treatment was started. This was somewhat reversible with L-taurine treatment, or minimally progressive. The mechanism of injury to the retina may be induced by elevations of γ-aminobutyric acid causing peripheral photoreceptor and ganglion cell damage, and this can be exacerbated by the use of vigabatrin. The use of taurine supplementation in tandem with vigabatrin may allow reversal of retinopathy and mitigate or slow down further deterioration. Further prospective clinical trials are required to evaluate this further. We recommend starting L-taurine therapy together with vigabatrin if a trial of vigabatrin is commenced in a patient with SSADH deficiency. Close monitoring of visual fields or ERG is also recommended at baseline and during vigabatrin therapy.

Sphingolipid profile alters in retinal dystrophic P23H-1 rats and systemic FTY720 can delay retinal degeneration.

Retinal degeneration (RD) affects millions of people and is a major cause of ocular impairment and blindness. With a wide range of mutations and conditions leading to degeneration, targeting downstream processes is necessary for developing effective treatments. Ceramide and sphingosine-1-phosphate, a pair of bioactive sphingolipids, are involved in apoptosis and its prevention, respectively. Apoptotic cell death is a potential driver of RD, and in order to understand the mechanism of degeneration and potential treatments, we studied rhodopsin mutant RD model, P23H-1 rats. Investigating this genetic model of human RD allows us to investigate the association of sphingolipid metabolites with the degeneration of the retina in P23H-1 rats and the effects of a specific modulator of sphingolipid metabolism, FTY720. We found that P23H-1 rat retinas had altered sphingolipid profiles that, when treated with FTY720, were rebalanced closer to normal levels. FTY720-treated rats also showed protection from RD compared with their vehicle-treated littermates. Based on these data, we conclude that sphingolipid dysregulation plays a secondary role in retinal cell death, which may be common to many forms of RDs, and that the U.S. Food and Drug Administration-approved drug FTY720 or related compounds that modulate sphingolipid metabolism could potentially delay the cell death.

Macular cystoid spaces in patients with retinal dystrophy.

BACKGROUND: Non leaking macular cystoid spaces (MCS) are seen in some retinal dystrophies. Carbonic anhydrase inhibitor (CAI) treatment may reduce the size of MSC and improve vision. METHODS: A retrospective study of patients with retinal dystrophy with MCS seen between 2009 and 2013 at two sites. Patients had ophthalmic examination, optical coherence tomography (OCT) and genetic testing. Patients with vision worse than 20/30 were treated with CAI. Post treatment visual acuity (VA), central foveal zone (CFZ) thickness, and qualitative estimation of MCS size were assessed. RESULTS: Eighteen patients, 6-47 years old, were included. IVFA was performed in 15 (83%) patients. Of the 26 eyes in 13 patients who were treated and followed, VA improved in 15 eyes (58%) of 10 patients. Ten of these 15 eyes had decreased CFZ thickness and 9/10 showed qualitative MCS improvement. Regression analysis showed that change in CFZ thickness was not significantly predictive of change in final visual acuity (p = 0.405). Five of 15 eyes with improved VA had paradoxically increased CFZ thickness and 2/5 had enlarged MCS. Three of the treated eyes (11%) in two patients had decreased VA with decreased CFZ thickness and improved MCS in 2/3 eyes. Eight eyes (31%) in six patients showed no change in VA with decreased CFZ thickness in 6/8 eyes with improved MCS. Genetic testing showed mutations of NR2E3, XLRS, CRB1, GPR98 and CNGB1. CONCLUSION: Non-leaking MCS occur in a variety of retinal dystrophies. Therapy with topical or systemic CAI has variable efficacy and may result in VA improvement with or without qualitative improvement in MCS and CFZ thickness.

Experimental studies on medical treatments of retinal dystrophies with a particular focus on ABCA4 retinopathies.

Retinal dystrophies are a group of hereditary diseases varying in clinical and etiological aspects. The most common central retinal dystrophy is Stargardt's disease, which is mainly caused by mutations in the ABCA4 gene. Dysfunction of the ABCA4 gene product leads to accumulation of toxic metabolites of the visual cycle and consequently to the loss of photoreceptors and surrounding retinal pigment epithelial cells. This study summarizes various pharmacological attempts aimed at slowing the progression of retinal dystrophies, especially ABCA4 retinopathies.

Mitochondrial Protection by Exogenous Otx2 in Mouse Retinal Neurons.

OTX2 (orthodenticle homeobox 2) haplodeficiency causes diverse defects in mammalian visual systems ranging from retinal dysfunction to anophthalmia. We find that the retinal dystrophy of Otx2(+/GFP) heterozygous knockin mice is mainly due to the loss of bipolar cells and consequent deficits in retinal activity. Among bipolar cell types, OFF-cone bipolar subsets, which lack autonomous Otx2 gene expression but receive Otx2 proteins from photoreceptors, degenerate most rapidly in Otx2(+/GFP) mouse retinas, suggesting a neuroprotective effect of the imported Otx2 protein. In support of this hypothesis, retinal dystrophy in Otx2(+/GFP) mice is prevented by intraocular injection of Otx2 protein, which localizes to the mitochondria of bipolar cells and facilitates ATP synthesis as a part of mitochondrial ATP synthase complex. Taken together, our findings demonstrate a mitochondrial function for Otx2 and suggest a potential therapeutic application of OTX2 protein delivery in human retinal dystrophy.

Sorsby Fundus Dystrophy: Novel Mutations, Novel Phenotypic Characteristics, and Treatment Outcomes.

PURPOSE: To report novel TIMP3 mutations, and to characterize the ocular phenotype of Sorsby fundus dystrophy (SFD), including a novel early sign for the disease and to report the effect of anti-VEGF therapy. METHODS: Twenty-one probands of three unrelated families with SFD were investigated using wide-field imaging, confocal laser scanning ophthalmoscopy with autofluorescence imaging, optical coherence tomography (OCT), indocyanine green-angiography (ICG-A), and molecular diagnostic for causative mutations. RESULTS: Molecular genetic analysis revealed two novel (p.Tyr174Cys, p.Tyr177Cys) and one previously described (p.Tyr182Cys) missense mutations in TIMP3. In families with p.Tyr177Cys and p.Tyr182Cys, metamorphopsia and/or decrease in visual acuity were the initial symptoms occurring at approximately the sixth decade of life. The p.Tyr174Cys mutation carriers had first symptoms at approximately the third decade with dark adaptation problems and visual field defects. The ocular phenotype included drusen-like deposits, rapidly progressive geographic atrophy, choroidal neovascularization (CNV), and polypoidal choroidal neovascularization (PCV). Late disease manifestations were uniform with widespread chorioretinal atrophy, fibrosis, and choroidal thinning. Three asymptomatic young carriers of a TIMP3 mutation with otherwise normal findings on funduscopy and retinal imaging showed a characteristically reduced fluorescence on late-phase ICG-A images. This phenotypic sign was more pronounced and widespread in later disease stages. Patients with CNV or PCV showed a favorable response to therapy with intravitreally injected bevacizumab. CONCLUSIONS: This study expands the spectrum of mutations in the TIMP3 gene and associated phenotypic findings. Imaging using late-phase ICG-A may be useful for early identification of individuals at risk for developing SFD. Intravitreal anti-VEGF therapy if initiated timely is effective in SFD patients with CNV.

Retinal Dystrophy with Intraretinal Cystoid Spaces Associated with Mutations in the Crumbs Homologue (CRB1) Gene.

PURPOSE: To report the occurrence of intraretinal cystoid spaces presumably due to retinal degeneration caused by CRB1 mutations, and the response to treatment with carbonic anhydrase inhibitors. MATERIALS: Retrospective case series. METHODS: We report four patients with retinal degeneration and intraretinal cystoid spaces due to CRB1 mutation. Of these patients, three were treated with topical carbonic anhydrase inhibitors. One of these three patients was changed to oral carbonic anhydrase inhibitor. Best corrected visual acuity and quantitative and qualitative macular optical coherence tomography results were recorded. RESULTS: Three patients were compound heterozygous for CRB1 mutations, and one had two mutations one of which was not found in the father. A total of seven different mutations were detected. All patients treated with carbonic anhydrase inhibitors experienced an improvement in visual acuity and decreased central retinal thickness, except in one eye in which retinal thickness paradoxically increased. CONCLUSIONS: CRB1 mutations may be associated with intraretinal cystoid spaces. The use of carbonic anhydrase inhibitors can result in improved visual acuity in some patients.

Modeling retinal dystrophies using patient-derived induced pluripotent stem cells.

Retinal degenerative disease involving photoreceptor (PR) cell loss results in permanent vision loss and often blindness. Generation of induced pluripotent stem cell (iPSC)-derived retinal cells and tissues from individuals with retinal dystrophies is a relatively new and promising method for studying retinal degeneration mechanisms in vitro. Recent advancements in strategies to differentiate human iPSCs (hiPSCs) into 3D retinal eyecups with a strong resemblance to the mature retina raise the possibility that this system could offer a reliable model for translational drug studies. However, despite the potential benefits, there are challenges that remain to be overcome before stem-cell-derived retinal eyecups can be routinely used to model human retinal diseases. This chapter will discuss both the potential of these 3D eyecup approaches and the nature of some of the challenges that remain.

Microglia-Müller glia crosstalk in the rd10 mouse model of retinitis pigmentosa.

Retinitis pigmentosa refers to a large, genetically heterogeneous group of retinal dystrophies. This condition is characterized by the gradual onset of blindness due to progressive deterioration of the retina, a process that includes photoreceptor and retinal-pigmented-epithelium cell decay and death, microglial recruitment, reactive gliosis, and vascular disorganization and regression. We found that early in the degenerative process, the rd10 mouse retina exhibits high levels of photoreceptor cell death and reactive Müller gliosis. In explant cultures, both degenerative processes were abrogated by IGF-I treatment. Moreover, the beneficial effect of IGF-I was diminished by microglial depletion using clodronate-containing liposomes. Interestingly, in the absence of IGF-I, microglial depletion partially prevented cell death without affecting Müller gliosis. These findings strongly suggest a role for microglia-Müller glia crosstalk in neuroprotection. However, a subpopulation of microglial cells appears to promote neurodegeneration in the dystrophic retina. Our findings indicate that beneficial neuroprotective effects may be achieved through strategies that modulate microglial cell responses.