Stem cell-derived retinal pigment epithelium (RPE) and photoreceptors (PRs) have restored vision in preclinical models of human retinal degenerative disease. This review discusses characteristics of ...stem cell therapy in the eye and the challenges to clinical implementation that are being confronted today. Based on encouraging results from Phase I/II trials, the first Phase II clinical trials of stem cell-derived RPE transplantation are underway. PR transplant experiments have demonstrated restoration of visual function in preclinical models of retinitis pigmentosa and macular degeneration, but also indicate that no single approach is likely to succeed in overcoming PR loss in all cases. A greater understanding of the mechanisms controlling synapse formation as well as the immunoreactivity of transplanted retinal cells is urgently needed.
Two questions that clinicians should answer as they attempt to apply the results of clinical trials to clinical practice are: (1) will statistically significant results be reproduced in their ...clinical practice; and (2) if nothing goes wrong in a clinical trial, is everything alright? Regarding the first question, when considering the results of a randomized, multicenter, prospective, controlled clinical trial, two questions that cannot be addressed by simply by reading the trial results and that only the practicing clinician can answer are: (1) is the study population representative of the patient about to be treated; and (2) is the totality of evidence outside the trial (including the clinician's own extensive experience) consistent with the trial result? Regarding the second question, clinicians are advised to recognize that most studies, even Phase 3 trials, are underpowered to accurately assess the risk of low frequency events.
Abstract Trophic factors are endogenously secreted proteins that act in an autocrine and/or paracrine fashion to affect vital cellular processes such as proliferation, differentiation, and ...regeneration, thereby maintaining overall cell homeostasis. In the eye, the major contributors of these molecules are the retinal pigment epithelial (RPE) and Müller cells. The primary paracrine targets of these secreted proteins include the photoreceptors and choriocapillaris. Retinal degenerative diseases such as age-related macular degeneration and retinitis pigmentosa are characterized by aberrant function and/or eventual death of RPE cells, photoreceptors, choriocapillaris, and other retinal cells. We discuss results of in vitro and in vivo animal studies in which candidate trophic factors, either singly or in combination, were used in an attempt to ameliorate photoreceptor and/or retinal degeneration. We also examine current trophic factor therapies as they relate to the treatment of retinal degenerative diseases in clinical studies.
Age-related macular degeneration (AMD) constitutes a prevalent, chronic, and progressive retinal degenerative disease of the macula that affects elderly people and cause central vision impairment. ...Despite therapeutic advances in the management of neovascular AMD, none of the currently used treatments cures the disease or reverses its course. Medical treatment of neovascular AMD experienced a significant advance due to the introduction of vascular endothelial growth factor inhibitors (anti-VEGF), which dramatically changed the prognosis of the disease. However, although anti-VEGF therapy has become the standard treatment for neovascular AMD, many patients do not respond adequately to this therapy or experience a slow loss of efficacy of anti-VEGF agents after repeated administration. Additionally, current treatment with intravitreal anti-VEGF agents is associated with a significant treatment burden for patients, caregivers, and physicians. New approaches have been proposed for treating neovascular AMD. Among them, designed ankyrin repeat proteins (DARPins) seem to be as effective as monthly ranibizumab, but with greater durability, which may enhance patient compliance with needed injections.
The choroidal vascularity index (CVI) is a relatively new parameter, calculated off optical coherence tomography (OCT) images, for the quantitative evaluation of choroid vascularity. It is defined as ...the ratio of vascular area to the total choroidal area, presented as a percentage. The choroid is an important vascular bed, often implicated in ocular and systemic conditions. Since the introduction of CVI, multiple studies have evaluated its efficacy as a tool for disease prognostication and monitoring progression, with promising results. The CVI was born out of the need for more robust and accurate evaluations of choroidal vasculature, as prior parameters such as choroidal thickness and choroidal vessel diameter had their limitations. In this review, we summarise current literature on the CVI, explain how the CVI is derived and explore its potential integration into future research and translation into clinical care. This includes the application of CVI in various disease states, and ongoing attempts to produce an automated algorithm which can calculate CVI from OCT images.
The angopoietin/tyrosine kinase with immunoglobulin and epidermal growth factor homology domains (Ang/Tie) pathway is an emerging key regulator in vascular development and maintenance. Its relevance ...to clinicians and basic scientists as a potential therapeutic target in retinal and choroidal vascular diseases is highlighted by recent preclinical and clinical evidence. The Ang/Tie pathway plays an important role in the regulation of vascular stability, in angiogenesis under physiological and pathological conditions, as well as in inflammation. Under physiological conditions, angiopoietin-1 (Ang-1) binds to and phosphorylates the Tie2 receptor, leading to downstream signalling that promotes cell survival and vascular stability. Angiopoietin-2 (Ang-2) is upregulated under pathological conditions and acts as a context-dependent agonist/antagonist of the Ang-1/Tie2 axis, causing vascular destabilisation and sensitising blood vessels to the effects of vascular endothelial growth factor-A (VEGF-A). Ang-2 and VEGF-A synergistically drive vascular leakage, neovascularisation and inflammation, key components of retinal vascular diseases. Preclinical evidence suggests that modulating the Ang/Tie pathway restores vascular stabilisation and reduces inflammation. This review discusses how targeting the Ang/Tie pathway or applying Ang-2/VEGF-A combination therapy may be a valuable therapeutic strategy for restoring vascular stability and reducing inflammation in the treatment of retinal and choroidal vascular diseases.
Open globe injury (OGI) is a severe form of eye trauma estimated at 2-3.8/100,000 in the United States. Most pediatric cases occur at home and are the result of sharp object penetration. The aim of ...this article is to review the epidemiology, diagnosis, management, and prognosis of this condition by conducting a systematic literature search with inclusion of all case series on pediatric OGI published between 1996 and 2015. Diagnosis of OGI is based on patient history and clinical examination supplemented with imaging, especially computed tomography when indicated. Few prospective studies exist for the management of OGI in pediatric patients, but adult recommendations are often followed with success. The main goals of surgical management are to repair the open globe and remove intraocular foreign bodies. Systemic antibiotics are recommended as medical prophylaxis against globe infection, or endophthalmitis. Other complications are similar to those seen in adults, with the added focus of amblyopia therapy in children. Severe vision decline is most likely due to traumatic cataracts. The ocular trauma score, a system devised to predict final visual acuity (VA) in adults, has proven to be of prognostic value in pediatric OGI as well. Factors indicating poor visual prognosis are young age, poor initial VA, posterior eye involvement, long wound length, globe rupture, lens involvement, vitreous hemorrhage, retinal detachment, and endophthalmitis. A thorough understanding of OGI and the key differences in epidemiology, diagnosis, management, and prognosis between adults and children is critical to timely prevention of posttraumatic vision loss early in life.
Blockade of vascular endothelial growth factor (VEGF) signaling, whether via sequestration of free VEGF or via inhibition of the tyrosine kinases activated by VEGF, is associated with decreased ...nitric oxide (NO) and prostaglandin-I 2 (PG-I 2) production along with vascular endothelial cell death. Systemic administration of drugs that block VEGF signaling (eg, for cancer treatment) is associated with systemic complications such as hypertension and thrombosis. Evidence regarding the risk of systemic serious adverse events after intravitreal injection of anti-VEGF agents in patients with diabetic macular edema or neovascular age-related macular degeneration is inconsistent, in part because of study design limitations (eg, bias of ascertainment through strict enrollment criteria and/or inadequate power to identify the risk of low frequency events). Studies involving patients at high risk of arteriothrombotic events (eg, patients with diabetic macular edema) who have high exposure to intravitreal anti-VEGF therapy (eg, monthly aflibercept or ranibizumab injection) demonstrate an increased risk of all-cause mortality compared with randomized controls. The pharmacokinetics of anti-VEGF drug clearance from the systemic circulation and the documented sustained reduction in free plasma VEGF levels after intravitreal aflibercept and bevacizumab injection are consistent with these findings. Although the frequency of systemic serious adverse events after intravitreal anti-VEGF therapy is low, some patients may be at higher risk (eg, those with recent stroke or multiple strokes), and physicians may wish to take special measures with these patients to minimize the risk of systemic complications.
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