A Cellular Approach to the Treatment of Diabetic Maculopathy

描述(申请人提供)：视网膜血管疾病，如糖尿病视网膜病变(DR)仍然是导致视力丧失和失明的常见原因。糖尿病会损害视网膜中的小血管，导致血管渗漏和闭塞，导致视力丧失。虽然有治疗糖尿病眼病的方法，但没有治疗受损的视网膜血管系统和视网膜缺血的治疗方法。视网膜缺血导致的视力丧失可能是永久性的和不可逆转的。一部分DR患者患有黄斑缺血，目前也没有有效的治疗方法。在过去的十年中，研究发现了一类骨髓来源的循环细胞，内皮祖细胞，它能够定位到血管病变并促进血管修复。然而，许多糖尿病患者的内皮祖细胞功能障碍，没有修复的潜力。在这项挑战赠款中，我们使用一种新的策略，建议纠正患有黄斑病变的糖尿病患者的功能障碍的EPC，并使用这些EPC来恢复缺血视网膜的灌流和纠正血管泄漏。为了解决知识上的关键差距，我们建议对50名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“机会之窗”。因此，我们提出了糖尿病黄斑缺血(DMI)和糖尿病黄斑水肿(DME)患者存在内皮祖细胞缺陷的假说，这种功能障碍可以通过瞬时抑制内皮祖细胞中的内源性转化生长因子-1(TGF-β1)来纠正。我们的具体目标将决定疾病自然历史上治疗患者的最佳时间，确定用于治疗的理想EPC人群，并确定最佳的眼部给药方法。在这项建议中，我们结合了临床研究、动物模型研究和使用针对转化生长因子-1的反义磷酸二酰吗啉低聚物(PMO)瞬时(2-4天)阻断糖尿病内皮细胞内源性转化生长因子-1的高度新颖的方法。这种治疗恢复了功能障碍的糖尿病细胞的修复能力。这项申请的调查人员代表来自工业界、私营部门和学术界的科学家。通过这种独特的组合，每个研究人员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。这项挑战赠款的结果将为糖尿病视网膜病变患者进行干细胞治疗的临床试验铺平道路。 公共卫生意义：我们的目标是开发一种有效、安全的糖尿病视网膜病变的临床治疗方法，使用患者血液中的干细胞，这些干细胞在患者体外被激活，然后返回修复眼睛中受损的血管。目前，还没有有效的治疗方法来逆转糖尿病视网膜病变，糖尿病视网膜病变的特征是由于缺乏视网膜的血液/氧气供应而导致视网膜血管损伤后视力丧失。

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.