Is there a drug therapy for age-related macular degeneration?--current status and new therapeutic approaches

Age-related macular degeneration (AMD) is the major cause of legal blindness in society today. In dry AMD age-related changes in Bruch's membrane and RPE result in the accumulation of cell debris with consequent degeneration. In the less common but more aggressive form, wet AMD, hypoxia and inflammation lead to an up-regulation of different growth factors such as VEGF resulting in formation of choroidal neovascularisation. Different therapeutic modalities have evolved to address this problem. Examples are photodynamic therapy to eradicate choroidal neovascularisation (CNV) via a physiochemical reaction or intravitreal application of anti-VEGF agents to stop leakage of fluid from the same CNV. The overall results have been either disappointing or not practical because of the necessity of chronic treatment. The treatment goal continues to evolve to that already realised in oncology which is for a cure. This mandates the investigation of combination strategies. Combination strategies should focus on utilising the differing mechanisms of action on the pathogenesis of the disease all the while minimising the side effects of the individual therapeutic agents.     

c-Kit-dependent growth of uveal melanoma cells: a potential therapeutic target?

PURPOSE: This study was conducted to investigate the expression and functional impact of the proto-oncogene c-kit in uveal melanoma. METHODS: Based on immunohistochemical (IHC) study of paraffin-embedded specimens from 134 uveal melanomas and Western blot analysis on eight fresh-frozen samples the expression of c-kit in uveal melanoma was studied. Furthermore, the phosphorylation of c-kit and the impact of the tyrosine kinase inhibitor STI571 was examined in the three uveal melanoma cell lines OCM-1, OCM-3, and 92-1. RESULTS: Eighty-four of 134 paraffin-embedded samples and six of eight fresh-frozen samples expressed c-kit. c-Kit was strongly expressed and tyrosine phosphorylated in cultured uveal melanoma cells compared with cutaneous melanoma cells. Moreover, in contrast to cutaneous melanoma cell lines c-kit maintained a high phosphorylation level in serum-depleted uveal melanoma cells. No activation-related mutations in exon 11 of the KIT gene were found. On the contrary, expression of the stem cell growth factor (c-kit ligand) was detected in all three uveal melanoma cell lines, suggesting the presence of autocrine (paracrine) stimulation pathways. Treatment of uveal melanoma cell lines with STI571, which blocks c-kit autophosphorylation, resulted in cell death. The IC(50) of the inhibitory effects on c-kit phosphorylation and cell proliferation was of equal size and less than 2.5 microM. CONCLUSIONS: The results confirm that c-kit is vastly expressed in uveal melanoma, suggest that the c-kit molecular pathway may be important in uveal melanoma growth, and point to its use as a target for therapy with STI571.     

Does macular hole formation have a hormonal cause?

PURPOSE: To establish the degree of supposed hormonal deficiency in estriadol (E2), gonadotrophins (LH, FSH), growth hormone (GH), insuline-like growth factor 1 (IGF-1) and to assess calcic-phosphatic metabolism in women with idiopathic macula holes as compared to (age-matched) controls. MATERIAL AND METHODS: In 16 female patients aged 65-72, blood E2, LH, FSH, IGF-1 were determined. Serum and 24 h urine excretion calcium and phosphates as well as serum alkaline phosphatase activity were taken as markers of Ca/P metabolism. Bone densitometry was performed in all. RESULTS: Mean actual serum hormone levels were: E2 < 15 pg/ml, LH--31 U/l, FSH--49 U/l, GH--0.1 ng/ml, IGF1--59 ng/ml. The markers of mineral metabolism did not show any abnormality: serum Ca--5.0 mEq/l, P--4.1 mg%, alkaline phosphatase 111 U/l, 24 h urine excretion Ca--121 mg/24 h, P--610 mg/24 h. Mean bone L2-L4 density fell within normal limits: 81% (z = -1.91). CONCLUSIONS: In postmenopausal women with idiopathic macular holes, serum E2, LH, FSH bone metabolic markers and bone density are comparable to those found in women (of the same age group) free of macular holes. Women with macular holes are characterized by lower GH and IGF-1, which prompts further study.     

COVID-19 and macular edema: a necessarily blindness?

Graefe's Archive for Clinical and Experimental Ophthalmology -     

Interferon alfa-2a: a new treatment option for long lasting refractory cystoid macular edema in uveitis? A pilot study

PURPOSE: To perform a prospective pilot study to evaluate interferon alfa-2a (IFN alfa-2a) for the treatment of refractory cystoid macular edema (CME) in endogenous uveitis. METHODS: IFN alfa-2a was administered at an initial dose of 3 or 6 million IU (depending on body weight) per day subcutaneously. Afterwards IFN alfa-2a was tapered slowly over 6 months and finally discontinued. If CME relapsed IFN alfa-2a was reinstituted and tapered slowly again to evaluate the lowest maintenance dose to keep remission. RESULTS: A total of 15 eyes of 8 patients with refractory CME due to intermediate or posterior uveitis were included. Ineffective pretreatment consisted of systemic steroids and acetazolamide (all patients) and at least one additional immunosuppressant (6 patients). Six of 8 patients (11 eyes) responded well to IFN alfa-2a and CME resolved completely during 6 months treatment. One patient was lost to follow-up after IFN alfa-2a was stopped. In 1 patient (1 eye) even 19 months after cessation of IFN alfa-2a no recurrence of CME occurred. In 4 patients (8 eyes) IFN alfa-2a had to be reinstituted because CME relapsed. All 4 patients responded again. During a mean follow-up period of 16.4 months since restart of therapy we succeeded in all 4 patients to taper IFN alfa-2a to maintenance doses between 1.5 million IU every second and every sixth day without a recurrence of CME in any of the 8 eyes. CONCLUSION: IFN alfa-2a can be a treatment option for patients with otherwise treatment resistant uveitic CME.     

Cholesterol and age-related macular degeneration: is there a link?

PURPOSE: To examine the relation among serum cholesterol, apolipoprotein E genotype (APOE), and the risk of early and late age-related macular degeneration (AMD). DESIGN: The Rotterdam Study, a population based prospective cohort study. METHODS: Serum levels of total and high-density lipoprotein (HDL) cholesterol as well as APOE genotype were determined at baseline. Of 3,944 subjects, 400 were diagnosed with incident early and late AMD after a mean follow-up of 5.2 years. RESULTS: Serum HDL, but not total, cholesterol was associated with an increased risk of AMD (odds ratio/SD, 1.20; 95% confidence interval; 1.06-1.35). The association remained unchanged after adjustment for APOE genotype. When stratifying for APOE genotype, the association was strongest in persons with the e 4 allele; an inverse association seemed to be present for e 2 carriers. CONCLUSION: Elevated HDL but not total cholesterol is associated with an increased risk of AMD. Apolipoprotein E genotype does not explain this association but may be an effect modifier.     

Is pseudophakia a risk factor for neovascular age-related macular degeneration?

PURPOSE: To examine the possible association between pseudophakia and neovascular age-related macular degeneration (AMD). METHODS: Reports of all patients undergoing fluorescein angiography in the authors' department over a 6-year period were retrospectively reviewed. Four hundred ninety-nine patients with recent onset of neovascular AMD in one eye and early age-related maculopathy (ARM) in the fellow eye were included in the study. Lens status (phakic or pseudophakic) in both eyes at the time of onset of neovascular AMD and the time between cataract surgeries (if performed) and onset of neovascular AMD were determined. RESULTS: There was no significant difference in lens status between eyes with neovascular AMD and fellow eyes with early ARM (115/499 [23.0%] vs. 112/499 [22.4%] pseudophakic; P = 0.88, odds ratio 1.035, 95% CI 0.770-1.391). Subgroup analysis revealed no difference between the groups with large drusen, small drusen, or pigmentary changes only (respectively, 20.3% vs. 19.6% pseudophakic, P = 0.92; 20.5% vs. 23.3% pseudophakic, P = 0.84; 33.3% vs. 31.7% pseudophakic, P = 1.0). Pseudophakic eyes with neovascular AMD had not been pseudophakic for a significantly longer period at the time of onset of neovascular AMD than their pseudophakic fellow eyes at the same time point (225.9 +/- 170.4 vs. 209.9 +/- 158.2 weeks, P = 0.27). CONCLUSIONS: The results do not support the hypothesis that pseudophakia is a major risk factor for the development of neovascular AMD.