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确定一种新的2-肾上腺素能受体激动剂(化合物49b)在预防和/或逆转非增殖性糖尿病视网膜病变方面的效力和疗效。糖尿病视网膜病变是导致工作年龄成年人失明的主要原因。自20世纪70年代S激光光凝术流行以来，目前对视网膜病变患者的治疗模式并没有明显改变。需要完成工作来开发一种新的治疗糖尿病视网膜病变的方法，以防止疾病从非增殖型发展到增殖型。我们有数据表明，消除对大鼠视网膜的交感神经传递可以复制非增殖性糖尿病视网膜病变的生化和组织学特征，这些特征在用β-肾上腺素能受体拮抗剂治疗大鼠时复制。我们现在已经在体外和体内证明，维持糖尿病大鼠视网膜中的β-肾上腺素能受体信号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，外用异丙肾上腺素的剂量范围很窄，不是一个商业上可行的产品。该提案中的项目将测试一种新型的β-肾上腺素能受体激动剂，用于局部应用来预防/逆转实验性非增殖性视网膜病变。在第一阶段的STTR中，我们将展示化合物49b在细胞培养和糖尿病大鼠中的急性疗效、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那些发生在人类受试者身上的研究。使用化学上新颖的化合物将增加工业和联邦资金的兴趣。该项目的可交付成果是Pre-IND启用数据，这些数据将促进化合物49b进入FDA批准和人体临床试验。 公共卫生相关性： 这项研究中提出的工作将测试一种新的治疗剂，通过局部应用来预防/治疗糖尿病视网膜病变。拟议的研究将证明化合物49b抑制糖尿病视网膜病变的有效性、安全性和有效性。

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