A Cellular Approach to the Treatment of Diabetic Maculopathy

描述（由申请人提供）：视网膜血管疾病，如糖尿病视网膜病变（DR）仍然是视力丧失和失明的常见原因。糖尿病会损害视网膜上的小血管，导致它们渗漏和闭塞，从而导致视力丧失。虽然治疗糖尿病眼病的各个方面是可用的，但治疗受损的视网膜血管和缺血性视网膜是可用的。视网膜缺血导致的视力丧失可能是永久性和不可逆的。DR患者的一个亚组患有黄斑缺血，目前也没有有效的治疗方法。过去十年的研究已经确定了一类骨髓来源的循环细胞，内皮祖细胞（EPCs），它们能够归巢到血管病变并促进血管修复。然而，许多糖尿病患者有功能失调的内皮细胞，没有修复的潜力。在本研究中，我们采用一种新的策略，建议纠正糖尿病黄斑病变患者的功能失调EPCs，并使用这些EPCs恢复缺血视网膜的灌注和纠正血管渗漏。为了解决知识上的关键空白，我们建议对50例糖尿病黄斑病变患者进行研究，以确定干细胞治疗成功的关键“机会窗口”。因此，我们提出糖尿病黄斑缺血（DMI）和糖尿病黄斑水肿（DME）患者存在EPCs缺陷，这种功能障碍可以通过短暂抑制EPCs中的内源性转化生长因子- 1 （TGF- 1）来纠正。我们的具体目标是确定疾病自然史中治疗患者的最佳时间，确定用于治疗的理想EPC人群，并确定最佳的眼部输送方法。在本研究中，我们结合了临床研究、动物模型研究和一种高度新颖的方法，即利用反义磷酸二酯morpholino oligomers （PMO）对TGF-¿1进行瞬时（2-4天）阻断糖尿病EPCs中的内源性TGF-¿1。这种治疗恢复了功能失调的糖尿病细胞的修复能力。这项应用程序的研究人员代表了来自工业界、私营部门和学术界的科学家。通过这种独特的组合，每个研究者都带来了特定的专业知识，包括干细胞生物学，临床视网膜专业知识和人类疾病的动物模型。这项挑战拨款的结果将为糖尿病视网膜病变患者干细胞治疗的临床试验铺平道路。

DESCRIPTION (provided by applicant): Retinal vascular diseases, such as diabetic retinopathy (DR) remain a common cause of vision loss and blindness. Diabetes can damage the small blood vessels in the retina causing them to leak and occlude resulting in vision loss. Although treatments are available for aspects of diabetic ocular disease no therapy is available to treat the damaged retinal vasculature and ischemic retina. Vision loss from retinal ischemia can be permanent and irreversible. A subgroup of DR patients suffer from macular ischemia and currently there is also no effective therapy. Research over the last decade has identified a class of bone marrow-derived circulating cells, endothelial progenitor cells (EPCs), which are capable of homing to vascular lesions and facilitating vascular repair. However, many diabetic patients have dysfunctional EPCs with no reparative potential. In this Challenge Grant using a novel strategy, we propose to correct dysfunctional EPCs of diabetic patients with maculopathy and use these EPC to both restore perfusion to the ischemic retina and correct vessel leaking. To address key gaps in knowledge, we propose to study 50 patients with diabetic maculopathy to define the critical 'window of opportunity' for stem cell treatment success. Thus, we propose the hypothesis that patients with diabetic macular ischemia (DMI) and diabetic macular edema (DME) have defective EPCs and this dysfunction can be corrected by transiently inhibiting endogenous transforming growth factor-¿ 1 (TGF-¿1) in the EPCs. Our specific aims will determine the best time in the natural history of the disease to treat the patient, identify the ideal EPC population to use for therapy, and determine the best method of delivery to the eye. In this proposal, we are using a combination of clinical studies, studies in animal models and the highly novel approach of transient (2-4 days) blockade of endogenous TGF-¿1 in diabetic EPCs using antisense phosphorodiamidate morpholino oligomers (PMO) to TGF-¿1. This treatment restores the reparative ability of the dysfunctional diabetic cells. The investigators of this application represent scientists from industry, from the private sector and from academia. With this unique mix, each investigator brings specific expertise including stem cell biology, clinical retina expertise and animal models of human disease. The results of this Challenge Grant will pave the way for clinical trials of stem cell therapy in patients with diabetic retinopathy. PUBLIC HEALTH RELEVANCE: Our goal is to develop an efficient, safe clinical treatment for diabetic retinopathy using stem cells from the patient's blood that have been activated outside of the patient then returned to repair damaged vessels in the eye. Currently, no effective treatment exists to reverse diabetic retinopathy marked by vision loss following retinal blood vessel damage caused by a lack of blood/oxygen supply to the retina.