Leber congenital amaurosis: disease, genetics and therapy.

Leber congenital amaurosis (LCA) is a congenital retinal dystrophy that was first described almost 150 years ago. LCA still remains an important cause of blindness with about 20% of children in schools for the blind being affected by it. LCA has genetic heterogeneity and the study of this disease is elucidating the genetics and molecular interactions involved in the development of the retina. This paper reviews the clinical history of the disease since it was first described. We further discuss the differential diagnosis of the disease and the difficulties encountered in making the diagnosis. We also review the genetics of the disease and the role of future therapies.

Erythropoietin promotes survival of retinal ganglion cells in DBA/2J glaucoma mice.

PURPOSE: Retinal ganglion cell (RGC) loss occurs in response to increased intraocular pressure (IOP) and/or retinal ischemia in glaucoma and leads to impairment of vision. This study was undertaken to test the efficacy of erythropoietin (EPO) in providing neuroprotection to RGCs in vivo. METHODS: The neuroprotective effects of EPO were studied in the DBA/2J mouse model of glaucoma. Mice were intraperitoneally injected with control substances or various doses of EPO, starting at the age of 6 months and continuing for an additional 2, 4, or 6 months. RGCs were labeled retrogradely by a gold tracer. IOP was measured with a microelectric-mechanical system, and EPO receptor (EPOR) expression was detected by immunohistochemistry. Axonal death in the optic nerve was quantified by para-phenylenediamine staining, and a complete blood count system was used to measure the number of erythrocytes. RESULTS: In DBA/2J mice, the average number of viable RGCs significantly decreased from 4 months to 10 months, with an inverse correlation between the number of dead optic nerve axons and viable RGCs. Treatment with EPO at doses of 3000, 6000, and 12,000 U/kg body weight per week all prevented significant RGC loss, compared with untreated DBA/2J control animals. EPO effects were similar to those of memantine, a known neuroprotective agent. IOP, in contrast, was unchanged by both EPO and memantine. Finally, EPOR was expressed in the RGC layer in both DBA/2J and C57BL/6J mice. CONCLUSIONS: EPO promoted RGC survival in DBA/2J glaucomatous mice without affecting IOP. These results suggest that EPO may be a potential therapeutic neuroprotectant in glaucoma.

VEGF164 is proinflammatory in the diabetic retina.

PURPOSE: The objectives of this study were to characterize the differential potency of two major VEGF isoforms, VEGF(120) and VEGF(164), for inducing leukocyte stasis (leukostasis) within the retinal vasculature and blood-retinal barrier (BRB) breakdown and to determine whether endogenous VEGF(164) mediates retinal leukostasis and BRB breakdown in early and established diabetes. METHODS: Retinal leukostasis and BRB breakdown were simultaneously quantified by combining concanavalin A lectin (ConA) perfusion labeling with a fluorophotometric dextran leakage assay. CD45 immunohistochemistry was performed to confirm that ConA-stained cells within the vasculature were leukocytes. Retinal leukostasis and BRB breakdown were compared in nondiabetic rats receiving intravitreous injections of VEGF(120) or VEGF(164). Retinal intercellular adhesion molecule (ICAM)-1 and VEGF protein levels were studied by Western blot and ELISA, respectively. An anti-VEGF(164(165)) aptamer (EYE001) was administered by intravitreous injection to 2-week and 3-month diabetic rats, and the effect on retinal leukostasis and BRB breakdown was quantified. RESULTS: Compared with VEGF(120), VEGF(164) more potently increased retinal ICAM-1 levels (2.2-fold), leukostasis (1.9-fold), and BRB breakdown (2.1-fold, P < 0.01 for all), despite negligible differences in vitreoretinal VEGF levels at the time of evaluation (P > 0.05). Retinal leukostasis and leakage increased with the duration of diabetes (P < 0.01) and correlated closely (P < 0.01, r = 0.889). The isoform-specific blockade of endogenous VEGF(164) with EYE001 resulted in a significant suppression of retinal leukostasis and BRB breakdown in both early (72.4% and 82.6%, respectively) and established (48.5% and 55.0%, respectively) diabetes (P < 0.01). CONCLUSIONS: On an equimolar basis, VEGF(164) is at least twice as potent as VEGF(120) at inducing ICAM-1-mediated retinal leukostasis and BRB breakdown in vivo. The inhibition of diabetic retinal leukostasis and BRB breakdown with EYE001 in early and established diabetes indicates that VEGF(164) is an important isoform in the pathogenesis of early diabetic retinopathy.

Intravitreal Foscarnet Therapy for Acyclovir-Resistant Acute Retinal Necrosis After Herpes Simplex Encephalitis.

The development of acute retinal necrosis (ARN) is not uncommon among individuals with a history of herpes simplex encephalitis, as the virus may be capable of transport via axonal cells to the neuroretina. Though it is known that ARN severely threatens vision, timely initiation of effective therapy can help save a patient's vision and retina. In this case report, clinical resistance to acyclovir was found. Subsequent treatment with intravitreal foscarnet resulted in immediate clinical improvement. This case suggests that patients with acute retinal necrosis can be considered for treatment with intravitreal foscarnet in the setting of systemic acyclovir resistance.

Role of c-Cbl-dependent regulation of phospholipase Cgamma1 activation in experimental choroidal neovascularization.

PURPOSE: Activation of phospholipase Cγ1 (PLCγ1) by vascular endothelial growth factor receptor (VEGFR)-2 is necessary for proliferation and tube formation of endothelial cells in vitro. Previous work has demonstrated that Casitas B-lineage lymphoma (c-Cbl) promotes ubiquitination of PLCγ1 and suppression of its tyrosine phosphorylation. This study was designed to evaluate the importance of PLCγ1 and c-Cbl in experimental choroidal neovascularization (CNV). METHODS: The role of PLCγ1 was studied in three models of angiogenesis: the endothelial cell culture system, the chorioallantoic membrane (CAM) assay, and the laser-induced CNV model. Endothelial cells were analyzed for the role of PLCγ1 in promoting tube formation. CAMs were incubated with pharmacologic agents that either inhibit or stimulate PLCγ1. CNV was induced in wild-type and c-Cbl-knockout mice, and the progression of CNV was evaluated by fluorescein angiography. RESULTS: Activation of PLCγ1 was necessary for tube formation of endothelial cells. PLCγ1 stimulation increased the growth of blood vessels and conversely, PLCγ1 inhibition decreased the growth of blood vessels in the CAM model. CNV lesions in the c-Cbl-knockout mice were significantly greater in number, more confluent, and increased in size with time, compared with those in the control wild-type mice. CONCLUSIONS: The data show that PLCγ1 plays an important role in angiogenesis. Loss of c-Cbl results in enhanced CNV in the eye. The study also shows that c-Cbl plays an important role in ocular angiogenesis, suggesting that modulation of c-Cbl activity or inhibition of PLCγ1 would be a compelling target for antiangiogenesis therapy.

Bevacizumab vs ranibizumab for age-related macular degeneration: early results of a prospective double-masked, randomized clinical trial.

PURPOSE: To report early outcomes of a prospective, double-masked, controlled trial comparing bevacizumab (Avastin; Genentech Inc, South San Francisco, California, USA) to ranibizumab (Lucentis; Genentech Inc) for the treatment of age-related macular degeneration. DESIGN: Prospective, double-masked, randomized clinical trial. METHODS: This is a single-center, randomized clinical trial at the Boston Veterans Affairs Healthcare System. Patients who met inclusion criteria were randomized 2:1 to bevacizumab or ranibizumab. Each patient contributed 1 eye to the study. All subjects and investigators (except for the pharmacist responsible for study assignments) were masked to treatment arms. Visual acuity (VA) was checked on Early Treatment Diabetic Retinopathy Study (ETDRS) chart. Patients were given either bevacizumab or ranibizumab every month for the first 3 months, followed by optical coherence tomography-guided, variable-dosing schedule. Main outcomes measured were VA and foveal thickness. RESULTS: Twenty patients completed the 6-month follow up. Thirteen patients received bevacizumab and 7 patients received ranibizumab. No subjects in either group lost more than 15 letters on ETDRS chart. The average preoperative VA was 31.6 letters in the bevacizumab group and 30.4 letters in the ranibizumab group. At 6 months follow-up, mean vision was 46.4 letters in the bevacizumab group and 37.4 letters in the ranibizumab group. Two-tailed ttest failed to show statistical significance between the two groups. Patients in the bevacizumab group underwent an average of 5 injections, while patients in the ranibizumab group underwent a mean of 4 injections. CONCLUSION: Early results of a head-to-head, randomized, double-masked, prospective, single-center controlled trial between bevacizumab and ranibizumab show no difference in efficacy between the two treatments for choroidal neovascularizaton in the treatment of age-related macular degeneration. As this study conveys results of a small number of patients, further studies with larger sample sizes are needed in order to establish statistical significance.