Novel Topical Therapy for Diabetic Retinopathy using Beta-Adrenergic Receptor Ago

描述（由申请人提供）： 我们工作的总体目标是建立一种新型2-肾上腺素能受体激动剂（化合物49 b）在预防和/或逆转非增殖性糖尿病视网膜病变中的效力和功效。糖尿病视网膜病变是导致工作年龄成人失明的主要原因。自20世纪70年代激光光凝术流行以来，目前视网膜病患者的治疗模式没有显著变化。需要完成的工作，以开发一种新的治疗糖尿病视网膜病变，防止疾病的进展，从非增殖形式的增殖形式。我们有数据表明，消除交感神经传递到大鼠视网膜再现非增殖性糖尿病视网膜病变的生化和组织学特征，这是再现时，大鼠用β-肾上腺素能受体拮抗剂治疗。我们现在已经在体外和体内证明，在糖尿病大鼠视网膜中维持β-肾上腺素能受体信号传导可以抑制视网膜功能和形态的丧失。这种视觉功能的维持与炎性细胞因子水平的降低和胰岛素受体信号的增加有关。不幸的是，局部异丙肾上腺素具有窄的剂量范围，并且不是商业上可行的产品。本提案中的项目将测试一种新型β-肾上腺素能受体激动剂，用于局部应用，以预防/逆转实验性非增殖性视网膜病变。在该1期STTR中，我们将证明化合物49 b在细胞培养物和糖尿病大鼠中的急性功效、药代动力学和效力。这项工作将加快转化为患者护理，因为对糖尿病啮齿动物的功能研究将反映在人类受试者中进行的研究。化学上新颖的化合物的使用将使工业界和联邦基金的兴趣增加。该项目的可交付成果是pre-IND使能数据，将促进化合物49 b进入FDA批准和人体临床试验。 公共卫生相关性： 本研究中提出的工作将测试一种新的治疗剂，以预防/治疗糖尿病视网膜病变使用局部应用。所提出的研究将证明化合物49 b抑制糖尿病视网膜病变的功效、安全性和效力

DESCRIPTION (provided by applicant): The overall goal of our work is to establish the potency and efficacy of a novel 2-adrenergic receptor agonist (compound 49b) in the prevention and/or reversal of non-proliferative diabetic retinopathy. Diabetic retinopathy is the leading cause of blindness in working age adults. The current treatment paradigm for retinopathy patients has not changed significantly since laser photocoagulation became popular in the 1970's. Work needs to be completed to develop a novel treatment for diabetic retinopathy that prevents the progression of the disease from the non-proliferative form to the proliferative form. We have data demonstrating that elimination of sympathetic neurotransmission to the rat retina reproduces the biochemical and histological features of non-proliferative diabetic retinopathy, which were reproduced when rats were treated with a beta-adrenergic receptor antagonist. We have now demonstrated both in vitro and in vivo that maintenance of beta- adrenergic receptor signaling in the diabetic rat retina can inhibit the loss of retinal function and morphology. This maintenance of visual function was associated with a decreased level of inflammatory cytokines and increased insulin receptor signaling. Unfortunately, topical isoproterenol has a narrow dose range and is not a commercially viable product. The projects in this proposal will test a novel beta-adrenergic receptor agonist for topical application to prevent/reverse experimental non-proliferative retinopathy. In this phase 1 STTR, we will demonstrate acute efficacy, pharmacokinetics, and potency of compound 49b in cell culture and in diabetic rats. Translation of this work into patient care will be expedited, as functional studies on the diabetic rodents will mirror those studies that occur in human subjects. The use of chemically novel compounds will allow for increased interest from both industry and federal funding. The deliverables from this project are pre-IND enabling data that will facilitate movement of Compound 49b into FDA approval and human clinical trials. PUBLIC HEALTH RELEVANCE: The work proposed in this study will test a novel therapeutic agent to prevent/treat diabetic retinopathy using topical application. The proposed studies will demonstrate efficacy, safety and potency of compounds 49b to inhibit diabetic retinopathy