Ophthalmic drug discovery: novel targets and mechanisms for retinal diseases and glaucoma

Blindness affects 60 million people worldwide. The leading causes of irreversible blindness include age-related macular degeneration, retinal vascular diseases and glaucoma. The unique features of the eye provide both benefits and challenges for drug discovery and delivery. During the past decade, the landscape for ocular drug therapy has substantially changed and our knowledge of the pathogenesis of ophthalmic diseases has grown considerably. Anti-angiogenic drugs have emerged as the most effective form of therapy for age-related macular degeneration and retinal vascular diseases. Lowering intraocular pressure is still the mainstay for glaucoma treatment but neuroprotective drugs represent a promising next-generation therapy. This Review discusses the current state of ocular drug therapy and highlights future therapeutic opportunities.     

Retinopathy of prematurity: molecular pathology and therapeutic strategies

Retinopathy of prematurity (ROP) is an ischemia-induced proliferative retinopathy, which affects premature infants with low birth weight. It is a leading cause of visual impairment and blindness in children, and shares pathophysiological characteristics with other common ocular diseases such as diabetic retinopathy, central vein occlusion, and age-related macular degeneration. Pathologically similar inherited diseases such as Norrie disease suggest a possible genetic component in the susceptibility to ROP. The process of retinal neovascularization in ROP and in animal models of oxygen-induced retinopathy is complex, and involves angiogenic factors, such as vascular endothelial growth factor, and basement membrane components. Potential medical therapies for ROP, including modulators of angiogenic factors, inhibitors of basement membrane changes, endogenous inhibitors such as pigment epithelium derived factor, and anti-inflammatory drugs, have shown efficacy against neovascularization in several animal models. Some of these therapies are in clinical trials now for diabetic retinopathy and age-related macular degeneration, and in the future may prove efficacious for the treatment of ROP.     

Corneal cell culture models: a tool to study corneal drug absorption

In recent times, there has been an ever increasing demand for ocular drugs to treat sight threatening diseases such as glaucoma, age-related macular degeneration and diabetic retinopathy. As more drugs are developed, there is a great need to test in vitro permeability of these drugs to predict their efficacy and bioavailability in vivo. Corneal cell culture models are the only tool that can predict drug absorption across ocular layers accurately and rapidly. Cell culture studies are also valuable in reducing the number of animals needed for in vivo studies which can increase the cost of the drug developmental process. Currently, rabbit corneal cell culture models are used to predict human corneal absorption due to the difficulty in human corneal studies. More recently, a three dimensional human corneal equivalent has been developed using three different cell types to mimic the human cornea. In the future, human corneal cell culture systems need to be developed to be used as a standardized model for drug permeation.     

New ocular therapeutics: a view from the patenting perspective

This feature article provides an overview of the newest therapeutic developments for ocular diseases, based on patents and patent applications that were published in the 12-month period from November 2005 to October 2006. In contrast to peer-reviewed literature covering breakthroughs in basic science research, the patenting perspective discloses the intentions of the pharmaceutical industry for imminent drug development. Selected documents describing drug delivery, dry eye syndrome, ocular infections and lesions, glaucoma and age-related macular degeneration are discussed. The role of RNA interference, which is of particular interest in ophthalmology research, is also highlighted.     

Emerging drugs for ophthalmic diseases

The ocular system is crucial to survival. It is subject to many of the same diseases found in other organ systems (e.g., diabetes) as well as diseases of ageing (e.g., macular degeneration) and other diseases (e.g., myopia). This review describes ocular diseases which are treatable, or potentially treatable, by pharmacological intervention (e.g., glaucoma, ocular infection, ocular allergy, ocular inflammation, dry eye and retinal pathology). Presented is a background of these diseases, the medical need for therapy, and current and potential new treatments.     

Emerging drugs for ophthalmic diseases

The ocular system is crucial to survival. It is subject to many of the same diseases found in other organ systems (e.g., diabetes) as well as diseases of ageing (e.g., macular degeneration) and other diseases (e.g., myopia). This review describes ocular diseases which are treatable, or potentially treatable, by pharmacological intervention (e.g., glaucoma, ocular infection, ocular allergy, ocular inflammation, dry eye and retinal pathology). Presented is a background of these diseases, the medical need for therapy, and current and potential new treatments.     

Pharmacotherapy of age-related macular degeneration

Background: Age-related macular degeneration is the leading cause of blindness in the developed world. The number of persons with vision loss from age-related macular degeneration is projected to increase dramatically over the next few decades. Therefore, effective therapeutic and prophylactic agents are greatly needed. Objective: This article will discuss some of the newer treatment strategies that may help to reduce the incidence of visual loss from age-related macular degeneration. Some of these therapies and strategies can be implemented today, while many are hypothetical based on current laboratory data and ongoing clinical trials. Methods: A review of the literature and ongoing clinical trials was undertaken. Conclusion: Current therapies using antioxidants for prevention of the progression of age-related macular degeneration and anti-vascular endothelial growth factor therapies for neovascular age-related macular degeneration have given us tools for tackling this disease better and reducing the number of patients with vision loss. Combinations of some of the existing treatments and new forms of therapy may yet further decrease the treatment burden in the future.     

贝伐珠单抗应用于眼器官疾病的安全信号检测与分析

目的：挖掘贝伐珠单抗治疗眼器官疾病的药品不良事件（ADE）信号,为其眼部超说明书用药管理提供参考。方法：采用报告比值比法（ROR）结合压缩估计对美国不良反应数据库2010第1季度~2021年第1季度中适应症为眼器官疾病的贝伐珠单抗报告进行数据挖掘和安全信号检测。结果：共得到贝伐珠单抗相关的8056个报告,涉及2431份病例,病例数位列前5位的适应症为：年龄相关性黄斑变性、糖尿病性视网膜病变、视网膜静脉阻塞、黄斑水肿、脉络膜新生血管。其中女性（45.37%）多于男性（37.15%）且老年患者居多。总体共得119个ADE信号,涉及18个系统/器官,主要是眼器官。报告数及信号强度均在前30的信号中,眼内炎、失明、玻璃体飞蛾症、视网膜剥离、眼部感染发生最多;脑血管意外、心肌梗死、神经系统病变、动脉血栓形成是死亡风险高且报告数/信号强度在前30的信号。结论：贝伐珠单抗治疗眼器官疾病的ADE信号集中在眼部,可造成不同程度的视力损伤,而生命威胁大的事件多在眼外器官/系统,临床对其在眼病的超适应症使用应更为慎重且应严格管理。     

Current choice of treatments for neovascular AMD

Age-related macular degeneration is the leading cause of irreversible blindness in developed countries with the neovascular form accounting for the majority of severe vision loss in the disease. The management of wet age-related macular degeneration has improved drastically in the past decade as anti-VEGF agents took its place at the forefront of treatment. As the choice of therapy is based on a number of factors, this review summarizes the pivotal studies that brought these agents to use and compares the different agents currently available. This review also briefly describes the promising new therapies that are in development.     

Small-interfering RNAs (siRNAs) as a promising tool for ocular therapy

RNA interference (RNAi) can be used to inhibit the expression of specific genes in vitro and in vivo, thereby providing an extremely useful tool for investigating gene function. Progress in the understanding of RNAi-based mechanisms has opened up new perspectives in therapeutics for the treatment of several diseases including ocular disorders. The eye is currently considered a good target for RNAi therapy mainly because it is a confined compartment and, therefore, enables local delivery of small-interfering RNAs (siRNAs) by topical instillation or direct injection. However, delivery strategies that protect the siRNAs from degradation and are suitable for long-term treatment would be help to improve the efficacy of RNAi-based therapies for ocular pathologies. siRNAs targeting critical molecules involved in the pathogenesis of glaucoma, retinitis pigmentosa and neovascular eye diseases (age-related macular degeneration, diabetic retinopathy and corneal neovascularization) have been tested in experimental animal models, and clinical trials have been conducted with some of them. This review provides an update on the progress of RNAi in ocular therapeutics, discussing the advantages and drawbacks of RNAi-based therapeutics compared to previous treatments.     

New Techniques for Drug Delivery to the Posterior Eye Segment

Ocular drug delivery has become an increasingly important field of research especially when treating posterior segment diseases of the eye, such as age-related macular degeneration, diabetic retinopathy, posterior uveitis and retinitis. These diseases are the leading causes of vision loss in developed countries which require repeated long-term administration of therapeutic agents. New drugs for the medication of the posterior ocular segment have emerged, but most drugs are delivered by repeated intravitreal injections associated with ocular complications. Advances in ocular drug delivery system research are expected to provide new tools for the treatment of the posterior segment diseases, providing improved drug penetration, prolonged action, higher efficacy, improved safety and less invasive administration, resulting in higher patient compliance. This review provides an insight into the recent progress and trends in ocular drug delivery systems for treating posterior eye segment diseases, with an emphasis on transscleral iontophoresis.     

Advances in ocular drug delivery: emphasis on the posterior segment

Introduction: Recent advances in pharmacological therapies to treat ocular diseases such as glaucoma, age-related macular degeneration, diabetic macular edema and retinal vascular occlusions have greatly improved the prognosis for these diseases. Due to these advances in pharmacological therapy, there is a great deal of interest in minimally invasive delivery methods, which has generated rapid developments in the field of ocular drug delivery.

Areas covered: This review will summarize currently available and recent developments for ocular drug delivery to both the anterior and posterior segments. Modes of delivery, including topical, systemic, transcleral/periocular and intravitreal, will be discussed and corresponding examples will be given. This review will highlight the advantages and disadvantages of each mode of delivery and discuss strategies to address these issues.

Expert opinion: An ideal therapy should maintain effective levels of drug for the intended duration of treatment following a single application, yet a significant number of months of therapy may be required. There are numerous approaches under investigation to improve treatment options. From the use of novel biomaterial implants and depots for sustained release, to prodrug formations, to iontophoresis to improve drug delivery, the main emphasis will continue to be placed on less invasive, longer acting, sustained release formulations in the treatment of numerous ocular disorders.     

Ocular angiogenesis: translating preclinical indications to successful clinical development

Angiogenesis-related ocular diseases such as age-related macular degeneration (AMD) or diabetic retinopathy have a high socioeconomic impact in western countries and are the leading causes of blindness. Conventional treatment modalities for AMD are of limited success. Inhibition of new vessel formation and targeting of pathological vessels seem to be the best choice in AMD. A variety of animal models mimic the relevant aspects of choroidal neovascularisation (CNV) and allow for therapy screening. Preclinical and clinical studies show that a variety of different strategies are very promising. Stategies include inhibition or blocking of vascular endothelial growth factor, a key player in angiogenesis), blocking specific receptors, application of naturally occurring angiogenesis inhibitors and gene therapy. However, the multistep pathways involved in ocular angiogenesis suggest that a cocktail approach is required for effective long-term treatment and prevention of CNV.     

Regulatory aspects of drug approval for macular degeneration

Age-related macular degeneration (AMD) is the leading cause of blindness in developed countries with approximately 15 million people with the disease in the United States. AMD is characterized as a progressive degenerative disease of the macula. There are two forms of AMD: neovascular and non-neovascular. The non-neovascular form of AMD is more common and leads to a slow deterioration of the macula with a gradual loss of vision over a period of years. The neovascular form of the disease is responsible for the majority of cases of severe vision loss and is due to proliferation of abnormal blood vessels behind the retina. These blood vessels leak blood and fluid into the retina, which results in visual abnormalities. The development of these abnormal blood vessels is due in part to the activity of VEGF (vascular endothelial growth factor) and its inhibition is expected to impact on the onset and/or severity of vision loss associated with the proliferation of abnormal blood vessels. Age-related macular degeneration is an underserved treatment population. Visudyne (verteporfin for injection), Novartis Ophthalmics, is FDA approved for the treatment of patients with predominantly classic subfoveal choroidal neovascularization due to age-related macular degeneration, pathologic myopia or presumed ocular histoplasmosis. Pegaptanib sodium (Macugen, Eyetech Pharmaceuticals, Inc. and Pfizer, Inc.) is indicated for the treatment of neovascular (wet) age-related macular degeneration. This article will review the approval pathway for these two products and that required of future products indicated for macular degeneration.     

青光眼局部药物机制、应用及副作用

青光眼是一组以特征性视神经萎缩和视野缺损为共同特征的疾病，是一种常见的不可逆性致盲眼病。目前，已有手术、激光等多种治疗方法，但局部抗青光眼药物仍然是主要选择。本文主要对各类局部药物的作用机制、临床应用及其副作用进行综述，为青光眼药物进一步研究提供参考。     

A view on new drugs for macular degeneration

Estimates suggest that in Europe 2.3% of people older than 65 years have neovascular age-related macular degeneration, which can lead to loss of central vision. The condition is the leading cause of blindness in the estern world, and the third commonest worldwide. It is characterised by growth of new blood vessels beneath the retina (choroidal neovascularisation), a process stimulated by the secretion of vascular endothelial growth factor (VEGF).3 Two new drugs, pegaptanib sodium (Macugen - Pfizer) and ranibizumab (Lucentis -Novartis), that block the effects of VEGF are now licensed in the UK for patients with neovascular age-related macular degeneration. A third drug that inhibits VEGF activity, bevacizumab (Avastin - Roche), is also used for this condition but is licensed only for metastatic colorectal or breast cancer. Here we consider the role of pegaptanib, ranibizumab and bevacizumab in patients with neovascular age-related macular degeneration.     

Sustained-release ophthalmic drug delivery systems for treatment of macular disorders: present and future applications

Macular disease currently poses the greatest threat to vision in aging populations. Historically, most of this pathology could only be dealt with surgically, and then only after much damage to the macula had already occurred. Current pathophysiological insights into macular diseases have allowed the development of effective new pharmacotherapies. The field of drug delivery systems has advanced over the last several years with emphasis placed on controlled release of drug to specific areas of the eye. Its unique location and tendency toward chronic disease make the macula an important and attractive target for drug delivery systems, especially sustained-release systems. This review evaluates the current literature on the research and development of sustained-release posterior segment drug delivery systems that are primarily intended for macular disease with an emphasis on age-related macular degeneration.Current effective therapies include corticosteroids and anti-vascular endothelial growth factor compounds. Recent successes have been reported using anti-angiogenic drugs for therapy of age-related macular degeneration. This review also includes information on implantable devices (biodegradable and non-biodegradable), the use of injected particles (microspheres and liposomes) and future enhanced drug delivery systems, such as ultrasound drug delivery. The devices reviewed show significant drug release over a period of days or weeks. However, macular disorders are chronic diseases requiring years of treatment. Currently, there is no 'gold standard' for therapy and/or drug delivery. Future studies will focus on improving the efficiency and effectiveness of drug delivery to the posterior chamber. If successful, therapeutic modalities will significantly delay loss of vision and improve the quality of life for patients with chronic macular disorders.     

Promising new treatments for neovascular age-related macular degeneration

Angiogenesis, the growth of new blood vessels from existing blood vessels, is responsible for vision loss in a variety of ophthalmic diseases. In neovascular age-related macular degeneration (AMD), the leading cause for legal blindness in many industrialised countries, abnormal blood vessels grow in the macula and cause blindness. There are a number of factors important in the angiogenic cascade but VEGF-A has been implicated in recent years as the major factor responsible for neovascular and exudative diseases of the eye. Numerous antiangiogenic drugs are in development but anti-VEGF drugs have shown great promise in treating neovascular AMD and other ocular diseases, and many of these drugs have been adopted from oncology where antiangiogenic therapy is gaining wide acceptance. For the first time in neovascular AMD, anti-VEGF drugs have brought the hope of vision improvement to a significant proportion of patients. This review provides an overview on angiogenic mechanisms, potential antiangiogenic treatment strategies and different antiangiogenic drugs with special focus on neovascular AMD.     

Promising new treatments for neovascular age-related macular degeneration

Angiogenesis, the growth of new blood vessels from existing blood vessels, is responsible for vision loss in a variety of ophthalmic diseases. In neovascular age-related macular degeneration (AMD), the leading cause for legal blindness in many industrialised countries, abnormal blood vessels grow in the macula and cause blindness. There are a number of factors important in the angiogenic cascade but VEGF-A has been implicated in recent years as the major factor responsible for neovascular and exudative diseases of the eye. Numerous antiangiogenic drugs are in development but anti-VEGF drugs have shown great promise in treating neovascular AMD and other ocular diseases, and many of these drugs have been adopted from oncology where antiangiogenic therapy is gaining wide acceptance. For the first time in neovascular AMD, anti-VEGF drugs have brought the hope of vision improvement to a significant proportion of patients. This review provides an overview on angiogenic mechanisms, potential antiangiogenic treatment strategies and different antiangiogenic drugs with special focus on neovascular AMD.     

Recent advances in pharmacotherapy of glaucoma

Glaucoma is a slow progressive degeneration of the retinal ganglion cells (RGCs) and the optic nerve axons, leading to irreversible blindness if left undiagnosed and untreated. Although increased intraocular pressure is a major risk factor of glaucoma, other factors include increased glutamate levels, alterations in nitric oxide (NO) metabolism, vascular alterations and oxidative damage caused by reactive oxygen species. Glaucoma is the second leading cause of blindness globally, accounting for 12.3% of the total blindness. Glaucoma has been broadly classified as primary or secondary open-angle or angle-closure glaucoma. The primary goal in management of glaucoma is to prevent the risk factor, especially elevated intraocular pressure (IOP), using medications, laser therapy or conventional surgery. The first-line treatment of glaucoma usually begins with the use of a topical selective or nonselective blocker or a prostaglandin analog. Second-line drugs of choice include alpha-agonists and topical carbonic anhydrase inhibitors. Cholinergic agonists are considered third-line treatment options. When a single therapy is not sufficient to lower the IOP, a combination therapy is indicated. To enhance the patient compliance, drug delivery systems like electronic devices, ocular inserts, tansdermal and mechanical drug delivery systems have been developed. Use of viscoelastic agents in ophthalmic formulations, emulsions and soluble ophthalmic drug inserts (SODI) enhance patience compliance and ocular drug delivery in patients in long-term glaucoma therapy. For patients who do not respond to antiglaucoma medications, laser trabeculoplasty and incisional surgery are recommended. Several nutrients and botanicals hold promise for the treatment of glaucoma, but most studies are preliminary, and larger, controlled studies are required. Future directions for the development of a novel therapy glaucoma may target glutamate inhibition, NMDA receptor blockade, exogenously applied neurotrophins, open channel blockers, antioxidants, protease inhibitors and gene therapy.