Phase 1 Study of JNJ-81201887 Gene Therapy in Geographic Atrophy Secondary to Age-related Macular Degeneration.

OBJECTIVE: To evaluate the safety and tolerability of a single intravitreal injection of JNJ-81201887 (JNJ-1887) in patients with geographic atrophy (GA) secondary to advanced dry age-related macular degeneration (AMD). DESIGN: Phase 1, open-label, single-center, first-in-human clinical study. SUBJECTS: Adult patients (aged ≥50 years) with GA secondary to AMD in the study-treated eye (treated eye) with a best corrected visual acuity (BCVA) Snellen equivalent of 20/200 or worse in the treated eye (20/80 or worse after the first 3 patients), a total GA lesion size between 5 and 20 mm2 (2-8 disc area), and BCVA of 20/800 or better in fellow, non-treated eye were included. METHODS: Patients (N=17) were sequentially enrolled into low (3.56×1010 viral genome [vg]/eye; n=3), intermediate (1.07×1011 vg/eye; n=3), and high (3.56×1011 vg/eye; n=11) dose cohorts without steroid prophylaxis and assessed for safety and tolerability over 24 months. MAIN OUTCOME MEASURES: Safety and tolerability outcomes included assessment of ocular and non-ocular treatment-emergent adverse events (AEs) over 24 months. Secondary outcomes included GA lesion size and growth rate. RESULTS: Baseline patient characteristics were consistent with the disease under study, and all enrolled patients had foveal center-involved GA. JNJ-1887 was well tolerated across all cohorts, with no dose-limiting AEs. There were no serious or systemic AEs related to study intervention. Overall, 5/17 (29%) patients experienced 6 events of mild ocular inflammation related to study treatment; exam findings in all resolved, and AEs resolved in 4 of 5 patients following topical steroids or observation. One unresolved vitritis event, managed with observation, occurred in a patient with an unrelated fatal AE. No endophthalmitis or new-onset choroidal neovascularization was reported. GA lesion growth rate was similar among all cohorts over 24 months. For treated eyes in the high-dose cohort, GA lesion growth rate showed continued decline through 24 months, with a reduction in mean square root lesion growth from 0.211 mm at months 0-6 to 0.056 mm at months 18-24. CONCLUSIONS: All 3 studied doses of JNJ-1887 had a manageable safety profile through 24 months of follow-up. Further investigation of JNJ-1887 for the treatment of GA is warranted.

Analyzing the demographics of patients with uveitis in an indigent, urban population.

PURPOSE: To study the types of uveitis examined in a hospital serving indigent populations in need of low-cost care. METHODS: A retrospective chart review examined the electronic medical records of all patients with uveitis-related at Drexel Eye Physicians. Data collected included demographics, anatomic location of the uveitis, systemic disease associations, treatment modalities and insurance. Statistical analysis was performed using χ² or Fischer exact tests. RESULTS: 270 patients (366 eyes) were included for analysis, 67% of patients identified as African American. Most eyes (95.3%, N = 349) were treated with topical corticosteroid drops, and only 6 (1.6%) received an intravitreal implant. Immunosuppressive medications were started in 24 patients (8.9%). Nearly 80% depended to some extent on Medicare or Medicaid Assistance for treatment coverage. There was no association between insurance type and use of biologics or difluprednate. CONCLUSION: We found no association between insurance type and the prescription of medications for uveitis that should be used at home. There was a minimal number of patients prescribed medications for implantation in the office. The adherence of use of medications at home should be investigated.

A Drop in Hemoglobin as an Association with Pegylated Interferon Retinopathy: A Novel Pathophysiology.

PURPOSE: To describe the association of change in the baseline hemoglobin levels with the development of interferon (INF) retinopathy after the start of pegylated INF (PEG INF) and ribavirin for hepatitis C virus treatment. METHODS: This was a retrospective chart review conducted on 12 patients on PEG INF and ribavirin with baseline examination and follow-up during the treatment regimen: 6 developed INF-induced retinopathy and 6 patients were without retinopathy. Serial hemoglobin values for both the groups were recorded at the time of the retinopathy diagnosis in affected patients and the nadir in those without retinopathy. The total percent reduction of hemoglobin was calculated for both the groups. RESULTS: Hemoglobin concentration levels between control and INF retinopathy patients tended to be slightly lower in the group that developed retinopathy. There was no threshold hemoglobin concentration under which the rate of developing retinopathy significantly increased. Greater than 25% drop in hemoglobin conferred a statistically significant risk in the development of INF-associated retinopathy. CONCLUSION: Patients starting PEG INF and ribavirin require baseline testing and subsequent follow-up based on the rapidity of the decrease in hemoglobin levels to identify the development of retinopathy with treatment.

Randomized Placebo-Controlled Trial Evaluating the Ophthalmic Safety of Single-Dose Tafenoquine in Healthy Volunteers.

INTRODUCTION: Tafenoquine has been recently registered for the prevention of relapse in Plasmodium vivax malaria. OBJECTIVE: This study assessed the pharmacodynamic effects of 300-mg single-dose tafenoquine on the retina. METHODS: This phase I, prospective, multicenter, randomized, single-masked, placebo-controlled, parallel-group study was conducted between 2 February 2016 and 14 September 2017 at three US study centers. Adult healthy volunteers were randomized (2:1) to receive either a single 300-mg oral dose of tafenoquine or matched placebo on day 1. Ophthalmic assessments, including spectral domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF), were conducted at baseline and day 90 and evaluated for pre-determined endpoints by an independent, masked reading center. RESULTS: One subject in each group met the composite primary endpoint for retinal changes identified with SD-OCT or FAF, i.e., one out of 306 (0.3%) with tafenoquine, one out of 161 (0.6%) with placebo. Both cases had unilateral focal ellipsoid zone disruption at day 90 with no effect on best-corrected visual acuity. The tafenoquine-treated subject had this abnormality at baseline, and was enrolled in error. There was no difference in ophthalmic safety between tafenoquine and placebo. CONCLUSION: There was no evidence of any pharmacodynamic effect of 300-mg single-dose tafenoquine on the retina or any short-term clinically relevant effects on ophthalmic safety. This clinical trial is registered with ClinicalTrials.gov (identifier: NCT02658435).

Suppression of connexin 43 phosphorylation promotes astrocyte survival and vascular regeneration in proliferative retinopathy.

Degeneration of retinal astrocytes precedes hypoxia-driven pathologic neovascularization and vascular leakage in ischemic retinopathies. However, the molecular events that underlie astrocyte loss remain unclear. Astrocytes abundantly express connexin 43 (Cx43), a transmembrane protein that forms gap junction (GJ) channels and hemichannels. Cx channels can transfer toxic signals from dying cells to healthy neighbors under pathologic conditions. Here we show that Cx43 plays a critical role in astrocyte apoptosis and the resulting preretinal neovascularization in a mouse model of oxygen-induced retinopathy. Opening of Cx43 hemichannels was not observed following hypoxia. In contrast, GJ coupling between astrocytes increased, which could lead to amplification of injury. Accordingly, conditional deletion of Cx43 maintained a higher density of astrocytes in the hypoxic retina. We also identify a role for Cx43 phosphorylation in mediating these processes. Increased coupling in response to hypoxia is due to phosphorylation of Cx43 by casein kinase 1δ (CK1δ). Suppression of this phosphorylation using an inhibitor of CK1δ or in site-specific phosphorylation-deficient mice similarly protected astrocytes from hypoxic damage. Rescue of astrocytes led to restoration of a functional retinal vasculature and lowered the hypoxic burden, thereby curtailing neovascularization and neuroretinal dysfunction. We also find that absence of astrocytic Cx43 does not affect developmental angiogenesis or neuronal function in normoxic retinas. Our in vivo work directly links phosphorylation of Cx43 to astrocytic coupling and apoptosis and ultimately to vascular regeneration in retinal ischemia. This study reveals that targeting Cx43 phosphorylation in astrocytes is a potential direction for the treatment of proliferative retinopathies.

Epiretinal membranes in uveitic macular edema: effect on vision and response to therapy.

PURPOSE: To evaluate the effects of epiretinal membranes on the response of uveitic macular edema to therapy and on visual acuity outcomes. DESIGN: Retrospective case series. METHODS: One hundred four eyes of 77 patients with uveitic macular edema were identified at a tertiary care center. Epiretinal membranes were diagnosed when identified by 2 investigators' grading of spectral-domain optical coherence tomography and scored for the presence or absence of surface wrinkling. Outcomes included best-corrected visual acuity, central subfield thickness, and rates of macular edema improvement (>20% reduction in central subfield thickness) and resolution (reduction of central subfield thickness to <315 µm) at 3 and 6 months follow-up. RESULTS: Seventy-two eyes of 59 patients had an epiretinal membrane on presentation. Eyes without epiretinal membranes and with epiretinal membranes without surface wrinkling were not significantly different at presentation or at 3 and 6 months follow-up. Conversely, eyes with an epiretinal membrane with retinal surface wrinkling had a greater proportion of eyes with 20/200 or worse visual acuity at presentation, and had worse mean acuities at 3 months (20/94 vs 20/35 for eyes without an epiretinal membrane, P = .002) and at 6 months follow-up (20/110 vs 20/36 for eyes without an epiretinal membrane, P = .02). At 6 months of follow-up the mean central subfield thicknesses were: eyes without an epiretinal membrane, 338 ± 23 µm; and eyes with an epiretinal membrane and surface wrinkling, 405 ± 22 µm (P = .05). CONCLUSIONS: In eyes with epiretinal membranes and retinal surface wrinkling, uveitic macular edema had a poorer visual acuity response to medical therapy and thicker maculae at 6 months.

Encephalopathy, Chiasmal Compression, Ophthalmoplegia, and Diabetes Insipidus in Pituitary Apoplexy.

Pituitary apoplexy with haemorrhage is a potentially life-threatening condition, and a rare cause of third nerve palsies. The range of vision loss and ophthalmoplegia seen in cases of apoplexy reflects the variability of cranial structures compressed by mass effect. The pathophysiology of extraocular muscle limitation and facial paraesthesia occurs with compression of the cavernous sinus, which contains cranial nerves III, IV, VI, and the ophthalmic branch of V. Blood supply to adjacent structures may be also compromised, causing additional loss of function. This case report of a patient with diabetes insipidus and a third nerve palsy illustrates the anatomic basis of the presenting signs of pituitary apoplexy, and the necessity for prompt neuroimaging if it is suspected.

An outbreak of fungal endophthalmitis after intravitreal injection of compounded combined bevacizumab and triamcinolone.

IMPORTANCE: Our experience may be useful to other practitioners using compounded intravitreal agents, those suspecting infectious outbreaks, and those managing fungal endophthalmitis. OBJECTIVE: To describe a series of patients with fungal endophthalmitis following intravitreal injection of combined bevacizumab and triamcinolone acetonide prepared by the same compounding pharmacy. DESIGN AND SETTING: Noncomparative case series. PARTICIPANTS: Eight eyes of 8 patients who received an intravitreal injection of compounded combined bevacizumab-triamcinolone in a period of 3 weeks had subtle, nonspecific findings that were later diagnosed as fungal endophthalmitis. MAIN OUTCOME MEASURES: Visual acuity, response to antimicrobial therapy, and number of vitreoretinal surgical operations after diagnosis of fungal endophthalmitis. RESULTS: Eight patients developed endophthalmitis 41 to 97 days after receiving the intravitreal injection, which was prepared by the same compounding pharmacy. The injections occurred at the same location in New York. Treatment was based on clinical examination findings and knowledge of the etiology of the endophthalmitis. Eventually, all patients were treated with oral voriconazole. Five of 8 patients were initially treated with intravitreal antimicrobial agents. After 3 months of follow-up, visual acuities ranged from 20/50 to hand motions. Local, state, and federal health department officials were involved in investigating the source of the outbreak. CONCLUSIONS AND RELEVANCE: In the current study, we report a fungal endophthalmitis outbreak after intravitreal injection of contaminated, compounded combined bevacizumab-triamcinolone. In this series, Bipolaris hawaiiensis was the identified causative agent. The challenge of medical diagnosis, identification of the source of the outbreak, and management experience are highlighted in our series. Our experience may be useful to other practitioners using compounded intravitreal agents, those suspecting infectious outbreaks, and those managing fungal endophthalmitis.

Subretinal fluid in uveitic macular edema: effect on vision and response to therapy.

PURPOSE: To evaluate the effect of subretinal fluid (SRF), imaged with spectral-domain optical coherence tomography (SD-OCT), on visual acuity outcomes in cases of uveitic macular edema (ME), and to analyze the response of SRF and uveitic ME to therapy. DESIGN: Retrospective case series. METHODS: One hundred and one eyes of 75 patients with uveitic ME, as imaged by SD-OCT, were identified at a single tertiary-care referral center. The main outcome measures were best-corrected visual acuity, central subfield thickness (CSFT), and rates of macular edema improvement (≥20% reduction in CSFT), and resolution (defined as reduction of CSFT to <315 µm) of ME at 3 and 6 months follow-up. RESULTS: Forty eyes of 29 patients had SRF on SD-OCT at presentation, which was associated with greater macular thickness (mean CSFT 488 µm vs 362 µm, P = .0001) and worse visual acuity than ME without SRF (20/115 vs 20/51, P = .015). However, eyes with SRF responded more favorably to treatment, and at 3 and 6 months of follow-up they achieved greater rates of improvement and resolution of ME than eyes without SRF (77% improved and 50% resolved at 6 months, vs 20% and 13%, respectively; P = .003 and P = .017, respectively) and recovered to a similar level of visual acuity (20/62 vs 20/42 at 6 months, P = .54). CONCLUSIONS: SRF in uveitic ME is associated with thicker retinas and worse visual acuity on presentation but responds more favorably to treatment and displays greater rates of edema resolution and visual acuity improvement.

Rectus muscle flap tear as an independent cause of restricted motility.

Most published cases of rectus muscle flap tear have been associated with orbital trauma of various degrees of severity. When they accompany an orbital fracture, however, it is difficult to determine whether the flap tear is merely an incidental additional finding or a major contributing cause of the resulting restriction. How to treat the flap itself remains an open question. We report a 24-year-old man with an inferior rectus muscle flap tear caused by direct laceration of the muscle. The major finding was a "reverse leash" vertical restriction. Discarding the flap instead of reattaching it did not prevent a successful result. Our case supports the proposition that rectus muscle flap tear can be a restriction-producing entity.

GABA blockade unmasks an OFF response in ON direction selective ganglion cells in the mammalian retina.

One unique subtype of retinal ganglion cell is the direction selective (DS) cell, which responds vigorously to stimulus movement in a preferred direction, but weakly to movement in the opposite or null direction. Here we show that the application of the GABA receptor blocker picrotoxin unmasks a robust excitatory OFF response in ON DS ganglion cells. Similar to the characteristic ON response of ON DS cells, the masked OFF response is also direction selective, but its preferred direction is opposite to that of the ON component. Given that the OFF response is unmasked with picrotoxin, its direction selectivity cannot be generated by a GABAergic mechanism. Alternatively, we find that the direction selectivity of the OFF response is blocked by cholinergic drugs, suggesting that acetylcholine release from presynaptic starburst amacrine cells is crucial for its generation. Finally, we find that the OFF response is abolished by application of a gap junction blocker, suggesting that it arises from electrical synapses between ON DS and polyaxonal amacrine cells. Our results suggest a novel role for gap junctions in mixing excitatory ON and OFF signals at the ganglion cell level. We propose that OFF inputs to ON DS cells are normally masked by a GABAergic inhibition, but are unmasked under certain stimulus conditions to mediate optokinetic signals in the brain.

Light-induced changes in spike synchronization between coupled ON direction selective ganglion cells in the mammalian retina.

Although electrical coupling via gap junctions is prevalent among ganglion cells in the vertebrate retina, there have been few direct studies of their influence on the light-evoked signaling of these cells. Here, we describe the pattern and function of coupling between the ON direction selective (DS) ganglion cells, a unique subtype whose signals are transmitted to the accessory optic system (AOS) where they initiate the optokinetic response. ON DS cells are coupled indirectly via gap junctions made with a subtype of polyaxonal amacrine cell. This coupling underlies synchronization of the spontaneous and light-evoked spike activity of neighboring ON DS cells. However, we find that ON DS cell pairs show robust synchrony for all directions of stimulus movement, except for the null direction. Null stimulus movement evokes a GABAergic inhibition that temporally shifts firing of ON DS cell neighbors, resulting in a desynchronization of spike activity. Thus, detection of null stimulus movement appears key to the direction selectivity of ON DS cells, evoking both an attenuation of spike frequency and a desynchronization of neighbors. We posit that active desynchronization reduces summation of synaptic potentials at target AOS cells and thus provides a secondary mechanism by which ON DS cell ensembles can signal direction of stimulus motion to the brain.