A Cellular Approach to the Treatment of Diabetic Maculopathy

治疗糖尿病黄斑病的细胞方法

• 批准号: 7828808
• 负责人: Stephen Hollis Bartelmez
• 金额: $ 49.69万
• 依托单位: BETASTEM THERAPUETICS, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7828808
• 关键词: Academia; Address; Adoptive Transfer; Adult; Age; Animal Model; Area; Autologous; Blindness; Blood; Blood Cells; Blood Vessels; Blood capillaries; Bone Marrow; CD34 gene; CXCR4 gene; Cell Count; Cell Therapy; Cell physiology; Cells; Characteristics; Clinical; Clinical Research; Clinical Treatment; Clinical Trials; Cohort Studies; Degenerative Disorder; Development; Diabetes Mellitus; Diabetic Retinopathy; Diabetic mouse; Disease; Edema; Endothelial Cells; Ensure; Eye; Functional disorder; Generations; Goals; Grant; Growth; Homing; Human; Industry; Ischemia; Knowledge; Lesion; Longitudinal Studies; Methods; Modeling; Molecular Profiling; Mus; Newborn Infant; Oxygen; Pathologic; Pathology; Patients; Perfusion; Peripheral; Phenotype; Physiological; Population; Prevalence; Private Sector; Reperfusion Injury; Reperfusion Therapy; Research; Research Personnel; Retina; Retinal; Retinal Degeneration; Retinal Diseases; Role; SCID Mice; Scientist; Stem Cell Development; Stem cells; Subgroup; Techniques; Testing; Therapeutic; Time; Toxic effect; Transforming Growth Factors; Tube; Vascular Diseases; Vision; capillary; cytokine; diabetic; diabetic patient; disease natural history; disorder of macula of retina; effective therapy; human disease; in vivo; macula; macular edema; neovascularization; non-diabetic; novel strategies; paracrine; patient population; phosphorodiamidate morpholino oligomer; prospective; public health relevance; receptor; repaired; restoration; retina blood vessel structure; retinal damage; retinal ischemia; stem cell biology; stem cell therapy; success

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.

描述（由申请人提供）：视网膜血管疾病，例如糖尿病性视网膜病（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中的小血管，导致其渗漏和闭塞，从而导致视力丧失治疗。目前尚无治疗受损视网膜脉管系统和缺血性视网膜的疗法。视网膜缺血导致的视力丧失可能是永久性的。一部分 DR 患者患有黄斑缺血，目前还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，即内皮祖细胞 (EPC)，它们能够归巢。然而，许多糖尿病患者的 EPC 功能失调，没有修复潜力。在这项挑战资助中，我们建议使用一种新策略来纠正糖尿病患者功能失调的 EPC。并使用这些 EPC 来恢复缺血性视网膜的灌注并纠正血管渗漏。为了解决关键的知识空白，我们建议对 50 名糖尿病性黄斑病患者进行研究，以确定干细胞治疗成功的关键“机会之窗”。因此，我们提出这样的假设：糖尿病性黄斑缺血（DMI）和糖尿病性黄斑水肿（DME）患者的 EPC 有缺陷，这种功能障碍可以通过暂时抑制内源性生长转化因子-¿ EPC 中的 1 (TGF-¿1) 我们的具体目标将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 群体，并确定递送至患者的最佳方法。在这项提案中，我们结合了临床研究、动物模型研究和短暂（2-4 天）阻断内源性 TGF-¿ 1 在糖尿病 EPC 中使用 TGF-¿ 反义磷酸二酰胺吗啉寡聚物 (PMO) 1. 这种治疗方法可以恢复功能失调的糖尿病细胞的修复能力。通过这种独特的组合，每位研究人员都拥有包括干细胞生物学、临床视网膜专业知识在内的特定专业知识。该挑战资助的结果将为糖尿病视网膜病变患者的干细胞治疗临床试验铺平道路。 公共健康相关性：我们的目标是利用患者血液中的干细胞开发一种有效、安全的临床治疗方法，这些干细胞在患者体外被激活，然后返回以修复眼睛中受损的血管。目前，尚无有效的治疗方法。逆转糖尿病性视网膜病变，其特征是由于视网膜缺乏血液/氧气供应而导致视网膜血管损伤，导致视力丧失。