Progress of clinical therapies for dry age-related macular degeneration

INTRODUCTION

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in adults over 50 years of age. This is particularly worrying as the portion of the population in this age range is rapidly increasing. In fact, the number of people in the United States aged 65y and older is expected to reach 82.7 million by 2050, more than doubling 2005 levels. More relevantly, a study designed to model AMD prevalence over time predicted that the number of early AMD cases may increase from 9.1 million in 2010 to 17.8 million in 2050, highlighting the urgency for continued research efforts to address the unmet needs of these patients.There are two forms of AMD, the dry (non-exudative) and wet(exudative) types. Wet AMD occurs when the choroid layer of the retina develops neovascularization. These new vessels are not as robust as well-established vasculature and, thus, become leaky to fluids, blood, and lipids which can penetrate the layers of the retina causing scar tissue and decreased cellular function. On the other hand, dry AMD is characterized by drusen deposition, pigment change and, in advanced stages,geographic atrophy of the macula. Geographic atrophy occurs when the layers of the macula become progressively thinner and less functioning. Due to the known molecular mechanisms that underlie wet AMD, there are several FDAapproved therapies to treat this form of the disease, whereas,dry AMD has no approved therapies. This is particularly concerning considering that the dry form of AMD is the most common type and accounts for more than 90% of diagnosed cases.

This review article will focus on clinical therapies being developed for the treatment of dry AMD, as this is the area most in need of treatment options for patients. Only therapies that have been at least evaluated in clinical trials will be discussed.

DRY AGE-RELATED MACULAR DEGENERATION THERAPIES

As progress in research provides new insight on mechanisms underlying the pathogenesis of dry AMD and uncovers new possible disease targets, a wide variety of potential therapeutic options are being developed.

Cell based therapies are generally divided into two types: stem cell-based and non-stem cellbased therapies. Both types of therapies take advantage of the immune-privileged environment of the subretinal space as a target, though they aim to affect this spacedifferent mechanisms. Stem cell-based therapies aim at replacing degenerated retinal pigment epithelium (RPE)cells by delivering healthy RPE cells into the subretinal space to preserve the health and function of the remaining photoreceptors and possibly support damaged light-sensitive cells to a return of function. The non-stem cell-based therapies,on the other hand, introduce cells that will release protective factors that are lacking in the extracellular environment to support photoreceptor survival and function. Aspects of cell therapy still actively researched are the optimal timing of transplantation, cell type to be targeted (choroidal endothelium,RPE, photoreceptors), and transplant product (encapsulated cell therapy, RPE with scaffold vs without scaffold) to name a few. The concerns with stem cell-based therapies include immune rejection, differentiation into undesired cell types,damage to surrounding tissues, and tumor formation. This section will look at cell-based therapies currently being trialed.Ocata Therapeutics (now acquired by Astellas Pharma)studied a stem cell-based therapy utilizing human embryonic stem cells (hESC)‐derived RPE. This trial employed the first generation of hESC-derived RPE cell line named MA09-hRPE. The Phase I/II study aimed at ascertaining the safety of subretinal transplantation of MA09-hRPE in a total of 18 patients (9 with Stargardt’s macular dystrophy and 9 with atrophic AMD). There were three dose treatments assessed(50 000, 100 000, and 150 000 cells). No evidence was found on adverse events such as proliferation, rejection, or serious ocular or systemic safety issues related to the transplanted cells. However, there were adverse events associated with vitreoretinal surgery and immunosuppression, one instance of which was a case of endophthalmitis. Seventy-two percent(13 of 18) of subjects had increased subretinal pigmentation consistent with transplanted RPE at the atrophic area border.At one-year post-treatment, visual function was improved in ten eyes, improved or remained stable in seven eyes, and decreased by more than ten letters in one eye, whereas the untreated fellow eyes showed no similar improvements in visual acuity. Optical coherence tomography (OCT)showed reconstitution or thickening of the RPE layer in some subjects. Another Phase II trial, also by Astellas entitled PORTRAY, was set to study MA09-hRPE cells in dry AMD.The study was specifically focused on graft rejection strategies,change in area of geographic atrophy, and visual acuity, but has been withdrawn for changes to the study design or cell line.Regenerative Patch Technologies is also studying implantation of hESC-derived RPE in the subretinal space, but they are utilizing a composite patch designated the California Project to Cure Blindness-Retinal Pigment Epithelium 1 (CPCB-RPE1).This composite patch consist of a polarized monolayer of hESC-RPE cells grown on an ultrathin, nonbiodegradable parylene substrate designed to simulate Bruch’s membrane.A Phase I/II trial enrolled 16 patients with advanced dry AMD resulting in geographic atrophy. None of the implanted eyes showed progression of vision loss and one eye improved by 17 letters. Preliminary results from this study reported potential therapeutic effects on visual acuity. There are two other clinical trials (in London and Japan) that are researching stem cell-derived RPE implantation but these studies occurred in patients with exudative AMD. Finally, a new trial is investigating autologous induced pluripotent stem cell (iPSCs)-derived RPE. Sponsored by the National Eye Institute, this Phase I/IIa clinical trial will assess the safety and feasibility of subretinal transplantation of iPSC-derived RPE grown as a monolayer on a biodegradable poly lactic-co-glycolic acid(PLGA) scaffold in patients with geographic atrophy. This trial is currently recruiting.

與國外的機構庫建設的高速發展相比，我國目前還處于起步階段。吳建中[3]2004年初發表文章探討了機構庫對圖書館整體管理模式的沖擊，將知識庫的概念引入我國。2005年7月，北京大學圖書館率領國內50多所高等院校圖書館聯合發表《圖書館合作與信息資源共享武漢宣言》，在宣言中明確指出我國高校圖書館應“建設特色館藏，開展特色服務，建立一批特色學術機構庫（Institutional Depository）”[4]。從那之后，機構知識庫的建設在國內，特別是我國高校圖書館逐步開啟[5]。

三是對家族制度也進行了批判。魏金枝還從經濟制度與人類生活入手，對家族制度的產生及其罪惡予以的批判。他說：

2.1兩種方法的療效比較置管引流組在住院天數、膿腔消失時間優于細針抽吸組,差異顯著(P<0.05)。見表1。

結果顯示，在親密關系喪失組被試中，高自尊者在職業認同及其職業行為、職業期望、職業情感維度上均顯著高于低自尊者，而在職業承諾、職業價值觀及職業認知方面無顯著差異，詳見表 8。

Several studies are designed to target the C5 component of the complement pathway. A Phase II clinical trial investigated intravitreal injections of LFG316 (a human IgG1 that targets C5 to inhibit the complement system) in subjects with geographic atrophy. The study consisted of 158 participants and was divided into 2 parts. Part A evaluated the safety and efficacy of multiple 5 mg/50 μL doses of intravitreal LFG316 against sham every 28d for 505 days; whereas Part B evaluated the safety and pharmacokinetics of a single intravitreal dose of 10 mg/100 μL of LFG316. At the conclusion of the clinical trial, the intravitreal LFG316 showed a tolerable safety profile but no improvement in either visual acuity or in preventing progression of geographic atrophy lesion. Another intravitreal C5 inhibitor, Zimura (avacincaptad pegol), sponsored by Iveric Bio, was studied in a Phase IIb randomized, controlled trial and met its prespecified primary endpoint of reducing the mean rate of geographic atrophy. The mean rate of geographic atrophy growth reduction over a year in the 2 mg group(compared to sham) was 27.38% (=0.0072). In the 4 mg group, the percentage was 27.81% (=0.0051). There were no reported adverse events and the trial will be moving into Phase 3.

It is important that studies involving stem cell-based therapies are approached in a manner that is safe and ethical for patients.As the potential of stem cell therapies increasingly raised hope in patients awaiting for a treatment, some clinics began offering the promise of stem cell‐assisted regeneration without going through the sanctioned channels of the FDA. This in turn generated much controversy in both the biomedical and general communities. Could unregulated stem cell-based treatments provide benefit to patients not approved for clinical trials? Possibly. Could it unnecessarily endanger patients desperate for a treatment? Probably. These questions are at the root of the controversy and came to full light with the SCOTS(Stem Cell Ophthalmology Treatment Study) study. The study reported fairly promising results of autologous bone marrowderived stem cells injected intravitreally as a potential therapy for dry AMD: after the treatment, 20 of 32 eyes experienced improvement in visual acuity averaging 27.6% on logMAR and ranging from 2.5% to 44.6% with a high statistical significance of≤0.001. Of the eyes treated, another 11 had visual acuity that remained stable and one had visual acuity that worsened as a result of natural disease progression rather than a complication of the SCOTS procedure. However,several patients receiving such autologous stem cell therapies as part of this or similar studies, have come forward claiming severe vision loss as a result of the treatment. In fact, in an article published in,three patients who received intravitreal injections of autologous adipose tissue-derived “stem cells” reported vision loss to a visual acuity ranging from 20/200 to no light perception(before injection visual acuity was 20/30 to 20/200). Large concern remains that, without rigorous oversight of clinical trials,patients may continue to receive unregulated therapies that puts them at risk of severe complications and unethical medical care.

Lampalizumab, a humanized monoclonal antibody, targets and inhibits complement factor D. Complement factor D is an enzyme that is the rate-limiting step in activation of the alternative complement pathway. A Phase II trial of lampalizumab suggested that it reduced the rate of geographic atrophy enlargement leading to a twin Phase III doublemasked, randomized, sham controlled clinical trials (Chroma and Spectri) that enrolled subjects across 275 sites in 23 countries for a total of 1881 subjects. These trials studied the safety and efficacy of an intravitreal injection of 10 mg of lampalizumab every 4 to 6wk versus sham injections.The results of these identical Phase III trials did not show a reduction in lesion progression compared to the sham treatment over 48wk.

由于永川區耕地后備資源缺乏, 建設用地擴展與耕地保護矛盾突出, 永川區農村居民點復墾應以增加耕地面積為主要目標。因此，根據前述方法和相關資料，計算出當前(2010年)永川區的土地資源承載力指數，同時結合相關學者的研究[19-21]以及永川區實際生態環境脆弱性情況，重新進行土地資源承載力等級劃分(如表3所示)；其次采用1/3法，將其規劃期間(2010-2020年)的復墾潛力系數劃分為高、中、低3個標準區間；最后，借助ArcGIS9.3工作平臺的疊加分析功能, 將永川區分為4類復墾區，分別命名為優先復墾區、重點復墾區、一般復墾區和適度復墾區(如表4和圖1所示)。……