Elliott H. Sohn

Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial

BACKGROUND Phase 1 studies have shown potential benefit of gene replacement in RPE65-mediated inherited retinal dystrophy. This phase 3 study assessed the efficacy and safety of voretigene neparvovec in participants whose inherited retinal dystrophy would otherwise progress to complete blindness. METHODS In this open-label, randomised, controlled phase 3 trial done at two sites in the USA, individuals aged 3 years or older with, in each eye, best corrected visual acuity of 20/60 or worse, or visual field less than 20 degrees in any meridian, or both, with confirmed genetic diagnosis of biallelic RPE65 mutations, sufficient viable retina, and ability to perform standardised multi-luminance mobility testing (MLMT) within the luminance range evaluated, were eligible. Participants were randomly assigned (2:1) to intervention or control using a permuted block design, stratified by age (<10 years and ≥10 years) and baseline mobility testing passing level (pass at ≥125 lux vs <125 lux). Graders assessing primary outcome were masked to treatment group. Intervention was bilateral, subretinal injection of 1·5 × 1011 vector genomes of voretigene neparvovec in 0·3 mL total volume. The primary efficacy endpoint was 1-year change in MLMT performance, measuring functional vision at specified light levels. The intention-to-treat (ITT) and modified ITT populations were included in primary and safety analyses. This trial is registered with ClinicalTrials.gov, number NCT00999609, and enrolment is complete. FINDINGS Between Nov 15, 2012, and Nov 21, 2013, 31 individuals were enrolled and randomly assigned to intervention (n=21) or control (n=10). One participant from each group withdrew after consent, before intervention, leaving an mITT population of 20 intervention and nine control participants. At 1 year, mean bilateral MLMT change score was 1·8 (SD 1·1) light levels in the intervention group versus 0·2 (1·0) in the control group (difference of 1·6, 95% CI 0·72-2·41, p=0·0013). 13 (65%) of 20 intervention participants, but no control participants, passed MLMT at the lowest luminance level tested (1 lux), demonstrating maximum possible improvement. No product-related serious adverse events or deleterious immune responses occurred. Two intervention participants, one with a pre-existing complex seizure disorder and another who experienced oral surgery complications, had serious adverse events unrelated to study participation. Most ocular events were mild in severity. INTERPRETATION Voretigene neparvovec gene replacement improved functional vision in RPE65-mediated inherited retinal dystrophy previously medically untreatable. FUNDING Spark Therapeutics.

Retinal neurodegeneration may precede microvascular changes characteristic of diabetic retinopathy in diabetes mellitus

Significance Diabetic retinopathy (DR), a primary cause of blindness, is characterized by microvascular abnormalities. Recent evidence suggests that retinal diabetic neuropathy (RDN) also occurs in people with diabetes, but little is known about the temporal relationship between DR and RDN. This longitudinal study in people with diabetes with no or minimal DR shows that RDN precedes signs of microvasculopathy and that RDN is progressive and independent of glycated hemoglobin, age, and sex. This finding was further confirmed in human donor eyes and in two experimental mouse models of diabetes. The results suggest that RDN is not ischemic in origin and represent a shift in our understanding of the pathophysiology of this complication of diabetes that potentially affects vision in all people with diabetes mellitus. Diabetic retinopathy (DR) has long been recognized as a microvasculopathy, but retinal diabetic neuropathy (RDN), characterized by inner retinal neurodegeneration, also occurs in people with diabetes mellitus (DM). We report that in 45 people with DM and no to minimal DR there was significant, progressive loss of the nerve fiber layer (NFL) (0.25 μm/y) and the ganglion cell (GC)/inner plexiform layer (0.29 μm/y) on optical coherence tomography analysis (OCT) over a 4-y period, independent of glycated hemoglobin, age, and sex. The NFL was significantly thinner (17.3 μm) in the eyes of six donors with DM than in the eyes of six similarly aged control donors (30.4 μm), although retinal capillary density did not differ in the two groups. We confirmed significant, progressive inner retinal thinning in streptozotocin-induced “type 1” and B6.BKS(D)-Leprdb/J “type 2” diabetic mouse models on OCT; immunohistochemistry in type 1 mice showed GC loss but no difference in pericyte density or acellular capillaries. The results suggest that RDN may precede the established clinical and morphometric vascular changes caused by DM and represent a paradigm shift in our understanding of ocular diabetic complications.

Clinical Features of Tuberculous Serpiginouslike Choroiditis in Contrast to Classic Serpiginous Choroiditis

OBJECTIVE To compare distinctive clinical features of presumed tuberculous serpiginouslike choroiditis (Tb-SLC) with classic serpiginous choroiditis (SC) in patients living in a region that is nonendemic for tuberculosis. METHODS Retrospective comparative analysis of clinical features of 5 patients with recurrent Tb-SLC and 5 with SC. RESULTS All patients with recurrent Tb-SLC primarily emigrated from areas highly endemic for tuberculosis and had been unsuccessfully treated with steroids/immunosuppressive agents. Results of uveitis investigations were negative except for positive tuberculin skin test results. These patients received oral tuberculostatic drugs, without recurrences (follow-up, 6-91 months). The ocular involvement in Tb-SLC was mostly unilateral, with multiple irregular serpiginoid lesions involving the posterior pole and periphery but usually sparing the juxtapapillary area. All 5 cases had inflammatory cells in the vitreous. Patients with SC were from areas nonendemic for tuberculosis, had negative uveitis workup findings (including tuberculin skin test results), and were successfully managed with steroids/immunosuppressive agents (follow-up, 6-72 months) with no recurrence. Ocular involvement in SC was usually bilateral, rarely multifocal, and primarily involved the posterior pole, especially around the optic disc and extending contiguously to the macula. No patient with SC presented with vitritis. CONCLUSION In areas nonendemic for tuberculosis, SC can be clinically differentiated from Tb-SLC. Patients with Tb-SLC come from highly endemic regions, show significant vitritis, and often present with multifocal lesions in the posterior pole and periphery. Cases of SC, in contrast, reveal minimal or no vitritis and frequently show bilateral involvement with larger solitary lesions extending primarily from the juxtapapillary area and sparing the periphery.

Complement activation and choriocapillaris loss in early AMD: Implications for pathophysiology and therapy

Age-related macular degeneration (AMD) is a common and devastating disease that can result in severe visual dysfunction. Over the last decade, great progress has been made in identifying genetic variants that contribute to AMD, many of which lie in genes involved in the complement cascade. In this review we discuss the significance of complement activation in AMD, particularly with respect to the formation of the membrane attack complex in the aging choriocapillaris. We review the clinical, histological and biochemical data that indicate that vascular loss in the choroid occurs very early in the pathogenesis of AMD, and discuss the potential impact of vascular dropout on the retinal pigment epithelium, Bruchs membrane and the photoreceptor cells. Finally, we present a hypothesis for the pathogenesis of early AMD and consider the implications of this model on the development of new therapies.

Retinal pigment epithelial changes in chronic Vogt-Koyanagi-Harada disease: fundus autofluorescence and spectral domain optical coherence tomography findings

Purpose: The purpose of this study was to determine whether fundus autofluorescence (FAF) and spectral domain-optical coherence tomography (SD-OCT) imaging allow better assessment of retinal pigment epithelium and the outer retina in subjects with chronic Vogt-Koyanagi-Harada disease compared with examination and angiography alone. Methods: A cross-sectional analysis of a series of seven consecutive patients with chronic Vogt-Koyanagi-Harada disease undergoing FAF and SD-OCT was conducted. Chronic disease was defined as duration of intraocular inflammation >3 months. Color fundus photographs were correlated to FAF and SD-OCT images. The images were later correlated to fluorescein angiography and indocyanine green angiography. Results: All patients had sunset glow fundus, which resulted in no apparent corresponding abnormality on FAF or SD-OCT. Lesions with decreased autofluorescence signal were observed in 11 eyes (85%), being associated with loss of the retinal pigment epithelium and involvement of the outer retina on SD-OCT. In 5 eyes (38%), some of these lesions were very subtle on clinical examination but easily detected by FAF. Lesions with increased autofluorescence signal were seen in 8 eyes (61.5%), showing variable involvement of the outer retina on SD-OCT and corresponding clinically to areas of retinal pigment epithelium proliferation and cystoid macular edema. Conclusion: Combined use of FAF and SD-OCT imaging allowed noninvasive delineation of retinal pigment epithelium/outer retina changes in patients with chronic Vogt-Koyanagi-Harada disease, which were consistent with previous histopathologic reports. Some of these changes were not apparent on clinical examination.

Combination Therapy for Neovascular Age-related Macular Degeneration Refractory to Anti-Vascular Endothelial Growth Factor Agents

OBJECTIVE To examine the outcomes of combination anti-vascular endothelial growth factor (VEGF) and photodynamic therapy (PDT) for the treatment of neovascular age-related macular degeneration (AMD) refractory to anti-VEGF monotherapy. DESIGN Retrospective, interventional case series. PARTICIPANTS Twenty-six eyes of 26 patients treated with anti-VEGF monotherapy for neovascular AMD with persistent subretinal or intraretinal fluid after at least 3 anti-VEGF injections in the 7 months before combination treatment. INTERVENTION Combination anti-VEGF treatment and PDT. MAIN OUTCOME MEASURES Visual acuity at 1 or 2, 3, and 6 months and central retinal thickness at 1 or 2, 3, and 6 months. Secondary outcome measures were change in number of fluid-free visits and interval between treatments in the 7 months before and 6 months after combination therapy. RESULTS Statistically significant improvements in logarithm of the minimum angle of resolution visual acuities were present at 1 month (P = 0.01) and 3 months (P = 0.01). Significant decreases in central subfield retinal thickness on optic coherence tomography (OCT) were seen at 1 month (P = 4×10(-5)), 3 months (P = 3×10(-4)), and 6 months (P = 4×10(-5)) as compared with precombination treatment OCT scans. The percentage of patient visits with no subretinal fluid increased from 0.5% to 41% after the initiation of combination therapy (P = 1×10(-5)). The interval between treatments increased from once every 1.6 months in the 7 months before combination treatment to once every 2.7 months in the 6 months after combination treatment (P = 0.002). No ocular complications attributable to PDT were seen. CONCLUSIONS Rescue therapy with the combination of anti-VEGF and PDT in eyes that have failed anti-VEGF monotherapy resulted in a mean improvement in vision, a decreased central subfield retinal thickness, and an increase in fluid-free intervals. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Three-dimensional Distribution of the Vitelliform Lesion, Photoreceptors, and Retinal Pigment Epithelium in the Macula of Patients With Best Vitelliform Macular Dystrophy

OBJECTIVE To describe the anatomical phenotypes of Best vitelliform macular dystrophy (BVMD) with spectral-domain optical coherence tomography (SD-OCT) in a large series of patients with confirmed mutations in the BEST1 gene. METHODS In our retrospective observational case series, we assessed 15 patients (30 eyes) with a clinical diagnosis of vitelliform macular dystrophy who were found to have mutations in the BEST1 gene. Color fundus photographs and SD-OCT images were evaluated and compared with those of 15 age-matched controls (30 eyes). Using a validated 3-dimensional SD-OCT segmentation algorithm, we calculated the equivalent thickness of photoreceptors and the equivalent thickness of the retinal pigment epithelium for each patient. The photoreceptor equivalent thickness and the retinal pigment epithelium (RPE) equivalent thickness were compared in all patients, in a region of the macula outside the central lesion for patients with BVMD and outside the fovea in control patients. Paired t tests were used for statistical analysis. RESULTS The SD-OCT findings revealed that the vitelliform lesion consists of material above the RPE and below the outer segment tips. Additionally, drusen-like deposition of sub-RPE material was notable, and several patients exhibited a sub-RPE fibrotic nodule. Patients with BVMD had a mean photoreceptor equivalent thickness of 28.3 μm, and control patients had a mean photoreceptor equivalent thickness of 21.8 μm, a mean difference of 6.5 μm (P < .01), whereas the mean RPE equivalent thickness was not statistically different between patients with BVMD and control patients (P = .53). CONCLUSIONS The SD-OCT findings suggest that vitelliform material is located in the subretinal space and that BVMD is associated with diffuse photoreceptor outer segment abnormalities overlying a structurally normal RPE. CLINICAL RELEVANCE These findings provide new insight into the pathophysiology of BVMD and thus have implications for the development of therapeutic interventions.

Structural and biochemical analyses of choroidal thickness in human donor eyes.

PURPOSE The choroid plays a vital role in the health of the outer retina. While measurements of choroid using optical coherence tomography show altered thickness in aging and macular disease, detailed histopathologic and proteomic analyses are lacking. In this study we sought to evaluate biochemical differences in human donor eyes between very thin and thick choroids. METHODS One hundred forty-one eyes from 104 donors (mean age ± standard deviation, 81.5 ± 12.2) were studied. Macular sections were collected, and the distance between Bruchs membrane and the inner surface of the sclera was measured in control, early/dry age-related macular degeneration (AMD), neovascular AMD, and geographic atrophy eyes. Proteins from the RPE-choroid of eyes with thick and thin choroids were analyzed using two-dimensional electrophoresis and/or mass spectrometry. Two proteins with altered abundance were confirmed using Western blot analysis. RESULTS Donor eyes showed a normal distribution of thicknesses. Eyes with geographic atrophy had significantly thinner choroids than age-matched controls or early AMD eyes. Proteomic analysis showed higher levels of the serine protease SERPINA3 in thick choroids and increased levels of tissue inhibitor of metalloproteinases-3 (TIMP3) in thin choroids. CONCLUSIONS Consistent with clinical imaging observations, geographic atrophy was associated with choroidal thinning. Biochemical data suggest an alteration in the balance between proteases and protease inhibitors in eyes that lie at the extremes of choroidal thickness. An improved understanding of the basic mechanisms associated with choroidal thinning may guide the development of new therapies for AMD.

Long-Term, Multicenter Evaluation of Subconjunctival Injection of Triamcinolone for Non-Necrotizing, Noninfectious Anterior Scleritis

PURPOSE We sought to characterize the long-term outcomes and complications of subconjunctival triamcinolone acetonide injection (STI) for non-necrotizing, noninfectious anterior scleritis. DESIGN Retrospective, interventional, noncomparative, multicenter study. PARTICIPANTS Sixty-eight eyes of 53 patients from 9 participating hospitals in the United States, Singapore, and Australia. Only eyes with 6 or more months of follow-up were included. INTERVENTION Subconjunctival injection of 2 to 8 mg of triamcinolone acetonide was administered to eyes with non-necrotizing, noninfectious anterior scleritis. MAIN OUTCOME MEASURES Resolution of signs and symptoms, time to recurrence of scleritis, and side effect profile. RESULTS Median follow-up was 2.3 years (range, 6 months to 8.3 years). Sixty-six eyes (97.0%) experienced improvement of signs and symptoms after 1 injection. Twenty-four months after a single injection, 67.6% of eyes remained recurrence-free, whereas at 48 months, 50.2% were recurrence-free. Some 55.0% of patients who had adverse effects from systemic medications were off all systemic medications at last follow-up; 55.0% of patients who were taking systemic medications at the time of first triamcinolone acetonide injection were not taking prednisone and immunosuppressants at this time; 76.2% of patients still requiring systemic agents had associated systemic disease. Fourteen eyes (20.6%) had ocular hypertension not requiring intraocular pressure (IOP)-lowering therapy. Two eyes (2.9%) were treated with topical IOP-lowering agents alone, and 2 eyes required surgical intervention for glaucoma. None developed scleral necrosis or melt. CONCLUSIONS This retrospective, international study carried out at 9 hospitals suggests that STI can treat non-necrotizing, noninfectious anterior scleritis with side effects limited to elevated IOP in a few patients. Although no cases of scleral melt or necrosis were observed, we cannot definitively conclude that this may not occur after STI. Intraocular pressure should be closely monitored after STI. Subconjunctival triamcinolone acetonide injection may be useful as adjuvant therapy or to decrease systemic medication burden. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Hand-held spectral domain optical coherence tomography finding in shaken-baby syndrome.

Purpose: The purpose of this study was to document the hand-held spectral domain optical coherence tomography (HHSD-OCT, Bioptigen, Durham, NC) findings in shaken-baby syndrome (SBS). The nonaccidental trauma in SBS has been associated with retinal findings, including hemorrhages in all layers of the retina and retinoschisis. Methods: Three consecutive patients with presumed SBS underwent complete ocular examination, fundus photography with the RetCam (Clarity Medical Systems, Pleasanton, CA), and imaging with the HHSD-OCT. Acquisition of the HHSD-OCT images required an assistant to stabilize the head of the infant. Results: All three patients had clinical findings consistent with SBS, including preretinal and intraretinal hemorrhages. Hand-held spectral domain optical coherence tomography documented focal posterior vitreous separation in four of the five eyes with multilayered retinoschisis in one eye, disruption of the foveal architecture and foveolar detachment in one eye, and disinsertion of the internal limiting membrane or inner retinoschisis in one eye. Hand-held spectral domain optical coherence tomography documented preretinal hemorrhages in all five eyes. Conclusion: Hand-held spectral domain optical coherence tomography is helpful in the evaluation of patients with SBS. All patients in our series had vitreoretinal abnormalities not detected on clinical examination, including, for example, multilayered retinoschisis. Hand-held spectral domain optical coherence tomography allows high-resolution imaging of the vitreoretinal interface and retina in infants with SBS and has provided insight into the mechanism of various retinal findings.