Development of a Novel Therapeutic for Diabetic Retinopathy

糖尿病视网膜病变新疗法的开发

基本信息

批准号：
9043771
负责人：
Tammy Z Movsas
金额：
$ 22.5万
依托单位：
ZIETCHICK RESEARCH INSTITUTE, LLC
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9043771
关键词：
Address Affect Anterior Antibodies Blindness Cell Line Characteristics Complications of Diabetes Mellitus Deterioration Development Diabetes Mellitus Diabetic Retinopathy Disease Effectiveness Eye Eyedrops Gonadotropin Receptors Gonadotropins Hormonal Hormone Antagonists Hormones Human Human Chorionic Gonadotropin Hypoxia Incidence Individual LH Receptors Lead Liquid substance Luteinizing Hormone Molecular Weight Onset of illness Operative Surgical Procedures Pathologic Patients Penetration Persons Phase Physicians Posterior eyeball segment structure Prevalence Procedures Process Production Research Institute Retina Retinal Retinal Detachment Retinal Diseases Retinal Neovascularization Risk Role Sampling Signal Pathway Small Business Innovation Research Grant Staging Therapeutic Topical application United States Up-Regulation Vascular Endothelial Growth Factors Vision Visual Visual impairment Vitrectomy Vitreous Hemorrhage Work aged base diabetic diabetic patient glycosylated HCG intravitreal injection laser photocoagulation molecular size non-diabetic novel novel strategies novel therapeutic intervention novel therapeutics prevent public health relevance receptor research clinical testing retina blood vessel structure retinal ischemia targeted treatment

项目摘要

DESCRIPTION (provided by applicant): Diabetes mellitus affects >380 million individuals worldwide and its incidence is increasing at alarming rates. Diabetic retinopathy (DR), the most common complication of diabetes, is the leading cause of new blindness in working-aged persons in the United States. Unfortunately, existing therapies are limited to advanced forms of DR. While therapeutic approaches such as laser photocoagulation, surgical vitrectomy and anti-angiogenic (anti-VEGF) agents treat some of the sight threatening complications, efficacy is inadequate as the disease has already progressed. There is a critical need for therapeutic approaches that act earlier in progression of DR, which would enable the physician to initiate treatment before the onset of visual deterioration. Zietchick Research Institute (ZRI) is investigating a potentially transformative therapeutic approach to addressing early stage DR. Based on work by our group and by others, there is strong support for the role of gonadotropins in upregulating vascular endothelial growth factor (VEGF) levels. High levels of VEGF are strongly associated with the retinal neovascularization that is characteristic of advanced DR. High intraocular VEGF levels have been mainly attributed to retinal ischemia; however, ZRI may have identified another mechanism for retinal VEGF upregulation (independent of hypoxia) via activation of a gonadotropin signaling pathway, that occurs upstream of VEGF production. Thus, targeting gonadotropin receptors may represent a new therapeutic approach for initiating treatment at early stage DR. In this Phase I SBIR proposal, we will assess the feasibility of targeting gonadotropin receptors to provide a DR therapeutic that could be implemented at early DR stage to prevent progression. In particular, we will determine the correlation between intraocular gonadotropin and VEGF levels in vitreous samples (extracted during vitrectomy surgery from diabetic and non-diabetic patients). We will also evaluate whether gonadotropins induces VEGF expression in a human retinal cell line, and furthermore, whether gonadotropin antagonists will inhibit this effect. Upon completion of this Phase I project, we will have demonstrated the feasibility of targeting a hormonal signaling pathway as a new therapeutic approach to addressing DR. In Phase II, ZRI will develop a (non-antibody-based) therapeutic of moderate molecular weight which will allow intraocular penetration. Thus, ZRI's therapeutic would be amenable to convenient and safe modes of administration (e.g., topical eye drop delivery). ZRI's approach has the potential to address the high unmet need for DR therapeutics that act earlier in the disease process before DR has reached its more advanced, vision-threatening form.

描述（由申请人提供）：糖尿病影响着全世界超过 3.8 亿人，其发病率正在以惊人的速度增加。糖尿病视网膜病变 (DR) 是糖尿病最常见的并发症，是导致工作年龄人口新发失明的主要原因。不幸的是，现有的治疗方法仅限于晚期形式的 DR，而激光光凝、手术玻璃体切除术和抗血管生成（抗 VEGF）药物等治疗方法可治疗某些疾病。视力威胁，由于疾病已经进展，因此迫切需要在 DR 进展早期发挥作用的治疗方法，这将使医生能够在视力恶化之前开始治疗。 ZRI）正在研究一种潜在的变革性治疗方法来解决早期 DR。根据我们小组和其他人的工作，促性腺激素在上调血管内皮生长因子 (VEGF) 水平方面的作用得到了强有力的支持。 VEGF 与视网膜新生血管形成密切相关，这是晚期 DR 的特征。高眼内 VEGF 水平主要归因于视网膜缺血；然而，ZRI 可能通过激活促性腺激素信号确定了视网膜 VEGF 上调（独立于缺氧）的另一种机制。因此，靶向促性腺激素受体可能代表了早期 DR 治疗的新治疗方法。在这一 I 期 SBIR 提案中，我们将评估靶向促性腺激素受体以提供可在早期 DR 阶段实施以预防进展的可行性，特别是，我们将确定玻璃体样本中眼内促性腺激素和 VEGF 水平之间的相关性。我们还将评估促性腺激素是否诱导人视网膜细胞系中的 VEGF 表达，以及此外，促性腺激素拮抗剂是否会抑制这种作用？在该一期项目完成后，我们将证明以激素信号通路作为解决 DR 的新治疗方法的可行性。因此，ZRI 的治疗方法将适合方便和安全的给药方式（例如，局部滴眼剂递送）。有望解决对 DR 疗法的高度未满足的需求，这些疗法在 DR 达到更高级、威胁视力的形式之前在疾病过程的早期发挥作用。