Emergence of dual VEGF and PDGF antagonists in the treatment of exudative age-related macular degeneration.
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ABSTRACT:
SUBMITTER: Kudelka MR
PROVIDER: S-EPMC6319892 | biostudies-literature | 2013
REPOSITORIES: biostudies-literature
Publications
Emergence of dual VEGF and PDGF antagonists in the treatment of exudative age-related macular degeneration.
Kudelka Matthew R MR Grossniklaus Hans E HE Mandell Kenneth J KJ
Expert review of ophthalmology 20130101 5
Neovascular ('wet') age-related macular degeneration (AMD) is the leading cause of blindness among Caucasians over the age of 55 in the USA and is an important cause of ocular morbidity worldwide. Progress in oncology, and more recently ophthalmology, led to the development of VEGF antagonists, three of which are now approved for the treatment of wet AMD. Recent discoveries in ophthalmology and vascular biology, however, suggest that combined inhibition of VEGF and platelet-derived growth factor ...[more]
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Project description:PurposeTo investigate the relationship between the early signs of age-related macular degeneration (AMD) and the risk of developing exudative AMD (typical AMD or polypoidal choroidal vasculopathy [PCV]) in the fellow eye of Japanese patients with unilateral exudative AMD, focusing particularly on eyes with only pigmentary abnormality.MethodsThis study is a retrospective observational consecutive case series. We retrospectively reviewed the medical charts of patients who revisited the AMD clinic from 2010 to 2011 and confirmed 129 cases with unilateral exudative AMD at their first visit (baseline). The non-affected eyes at baseline (the second eye) were categorized by the presence of early signs of AMD. The incidence of exudative AMD (typical AMD or PCV) in the fellow eye was confirmed by fluorescein and indocyanine green angiography.ResultsOf the 129 patients, 14 (10.9%) developed exudative AMD in the fellow eye (median follow-up, 3.2 years; n = 7 typical AMD and n = 7 PCV). Eyes with both pigmentary abnormalities and large drusen were more likely to develop typical AMD (age- and sex-adjusted odds ratio = 9.46, 95% confidence interval = 1.05 to 85.0), whereas pigmentary abnormalities without large drusen were associated with PCV (age- and sex-adjusted odds ratio = 15.9, 95% confidence interval = 1.8 to 140.5).ConclusionsThere was a difference in the association between early signs of AMD and incident development of either typical AMD or PCV. Further research is warranted to determine whether pigmentary abnormalities alone may be an important risk factor for PCV in Asians.
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Project description:Background and objectiveTo evaluate the safety and efficacy of intravitreal sirolimus for persistent, exudative age-related macular degeneration (AMD).MethodsThis institutional review board approved, registered (NCT02357342), prospective, subject-masked, single center, randomized controlled trial in subjects with persistent, exudative Age-related macular degeneration compared intravitreal sirolimus monotherapy (every 2 months) versus monthly anti-vascular endothelial growth factor (VEGF) over six months.Results20 subjects were randomized to each arm of the trial. Upon completion of the trial 20 patients were analyzed in the control (anti-vascular endothelial growth factor) group and 17 patients were analyzed in the treatment (sirolimus) group. On average, subjects had 33 previous anti-VEGF injections prior to entry. The primary end-point, mean central subfield thickness (CST), increased by 20 µm in the anti-vascular endothelial growth factor group and decreased by 40 µm in the sirolimus group (p?=?0.03). Visual acuity outcomes were similar between groups. Serious ocular adverse events in the sirolimus group included one subject each with anterior uveitis, central retinal artery occlusion and subretinal hemorrhage.ConclusionMonotherapy with intravitreal sirolimus for subjects with persistent, exudative age-related macular degeneration appears to have a limited positive anatomic benefit. The presence of adverse events in the experimental group merits further evaluation, potentially as an adjuvant therapy. Trial registration This trial was registered with the clinicaltrials.gov, NCT02357342, and was approved by the institutional review board at Advarra. Funding was provided by an investigator-initiated grant from Santen. Santen played no role in the design or implementation of this study.
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Project description:Non-exudative age-related macular degeneration, a prevalent cause of blindness, is a progressive and degenerative disease characterized by alterations in Bruch's membrane, retinal pigment epithelium, and photoreceptors exclusively localized in the macula. Although experimental murine models exist, the vast majority take a long time to develop retinal alterations and, in general, these alterations are ubiquitous, with many resulting from non-eye-specific genetic manipulations; additionally, most do not always reproduce the hallmarks of human age-related macular degeneration. Choroid vessels receive sympathetic innervation from the superior cervical ganglion, which, together with the parasympathetic system, regulates blood flow into the choroid. Choroid blood flow changes have been involved in age-related macular degeneration development and progression. At present, no experimental models take this factor into account. The aim of this work was to analyze the effect of superior cervical gangliectomy (also known as ganglionectomy) on the choroid, Bruch's membrane, retinal pigment epithelium and retina. Adult male C57BL/6J mice underwent unilateral superior cervical gangliectomy and a contralateral sham procedure. Although superior cervical gangliectomy induced ubiquitous choroid and choriocapillaris changes, it induced Bruch's membrane thickening, loss of retinal pigment epithelium melanin content and retinoid isomerohydrolase, the appearance of drusen-like deposits, and retinal pigment epithelium and photoreceptor atrophy, exclusively localized in the temporal side. Moreover, superior cervical gangliectomy provoked a localized increase in retinal pigment epithelium and photoreceptor apoptosis, and a decline in photoreceptor electroretinographic function. Therefore, superior cervical gangliectomy recapitulated the main features of human non-exudative age-related macular degeneration, and could become a new experimental model of dry age-related macular degeneration, and a useful platform for developing new therapies.
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Project description:Treatment of exudative age-related macular degeneration has been revolutionized within the last 6 years with the introduction of vascular endothelial growth factor neutralizing agents. Previously popular "destructive treatments," such as laser photocoagulation and photodynamic treatment have either been abandoned or used as an adjunct to pharmacotherapy. Despite the increase in vision after antivascular endothelial growth factor (VEGF) agents, they require repetitive and costly intravitreal injections that also carry the inherit risks of infection, retinal tears, and detachment. Several new and more potent VEGF inhibitors are at different stages of development. The goal of evolving pharmacotherapy is to preserve the therapeutic effect while reducing or eliminating the discomfort of intravitreal drug delivery, as well as identify new therapeutic targets. Complement inhibitors, immunomodulators, integrin inhibitors are a few of the new class of drugs that are expected to be in our armamentarium soon. Current medications act to decrease leakage through abnormal subretinal choroidal vasculature and promote involution. However, these medications are only effective in treating the active stage of the choroidal neovascular membrane. Restoration of vision of a large number of patients with involuted choroidal neovascular membranes is warranted. For this purpose, tissue engineering techniques have been employed to reconstruct the subretinal anatomy. Discovery of biomarkers, pharmacogenetics, and very specific targeting holds the promise of increased potency and safety in the future.
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