Evaluation of a Connexin-based Peptide for the Treatment of Diabetic Retinopathy

基于连接蛋白的肽治疗糖尿病视网膜病变的评价

基本信息

批准号：
10483702
负责人：
Christina Grek
金额：
$ 31.49万
依托单位：
XEQUEL BIO, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-30 至 2024-03-23
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10483702
关键词：
Adult Age Animal Model Apoptosis Bilateral Biodistribution Blindness Blood Preservation Blood Vessels Blood-Retinal Barrier Cell Communication Cells Characteristics Clinic Clinical Clinical Research Clinical Trials Clinical assessments Complications of Diabetes Mellitus Connexin 43 Connexins Data Development Diabetes Mellitus Diabetic Retinopathy Disease Drug Kinetics Effectiveness Endothelial Cells Epithelial Cells Evaluation Event Extravasation Eye Eyedrops Formulation Functional disorder Funding Gap Junctions Goals Health Histopathology Homeostasis Human Hyperglycemia In Vitro Inflammation Inflammatory Injury Integral Membrane Protein Intercellular Junctions Life Liquid substance Longitudinal Studies Medical Methods Modeling Morphology Nature Nerve Degeneration Pathogenesis Pathology Patients Peptides Pharmaceutical Preparations Phase Pre-Clinical Model Research Retina Safety Severity of illness Small Business Innovation Research Grant Streptozocin Structure of retinal pigment epithelium Testing Therapeutic Tight Junctions Tissues Topical application Toxicokinetics Translating Translations Treatment Side Effects Vascular Diseases Vascular Endothelial Cell Vascular Endothelial Growth Factors Vascular Permeabilities Visual Acuity Visual impairment base cell injury diabetic diabetic rat efficacy study healing improved outcome in vivo innovation intercellular communication intravitreal injection monolayer mouse model neovascularization peptide drug peptidomimetics preservation prevent regenerative safety study side effect standard of care therapeutic effectiveness therapeutic target type I diabetic vascular abnormality

项目摘要

Diabetic retinopathy (DR) is the leading cause of blindness and visual impairment in US adults. The current standard of care for DR is intravitreal (IVT) injection of anti-vascular endothelial growth factor (VEGF) therapeutics to inhibit vascular permeability and neovascularization. However, anti-VEGF drugs have limited efficacy in a substantial percentage of DR patients. The invasiveness of IVT injections also correlates with poor compliance as well as serious side effects. As such, there is an unmet medical need for an innovative noninvasive treatment that effectively mitigates DR pathogenesis and progression. In this research application, we propose to evaluate the therapeutic potential of a peptide-containing eye drop formulation (iNexin™) to mitigate DR pathophysiology by preserving blood-retina barrier (BRB) integrity. The BRB, which is formed by tight junctions of retinal vascular endothelial cells and retinal pigment epithelial cells, breaks down early in DR pathogenesis and causes vascular permeability and leakage as well as inflammation, leading to loss of retinal homeostasis and neurodegeneration. Diabetes-associated factors also disrupt gap junction intercellular communications to further exacerbate DR. Therefore, protecting intercellular junctions represents a significant therapeutic opportunity to treat DR. Connexin43 (Cx43) is a transmembrane protein component of intercellular junctions that is instrumental to barrier function integrity, cell-cell communication, and apoptosis. FirstString Research Inc. has developed a therapeutic peptide mimetic of Cx43, alpha-Connexin Carboxy-Terminal (aCT1), that stabilizes intercellular junctions while tempering hemichannel activity to preserve barrier function, reduce injury spread, and decrease inflammation. iNexin is a stable non-steroidal, preservative-free aCT1 eye drop formulation validated in a comprehensive set of safety and efficacy studies. From these studies, we hypothesize that iNexin treatment will stabilize intercellular junctions comprising the BRB to ameliorate DR pathophysiology, preserving retinal health and function. To test this hypothesis, we propose to demonstrate proof-of-concept efficacy of iNexin to mitigate diabetic retinopathy (Aim 1), and to confirm aCT1 biodistribution in the diabetic eye following eye drop administration (Aim 2). Using a translationally relevant streptozotocin-induced type 1 diabetic rat model, we propose to evaluate the impact of iNexin on DR using two distinct treatment paradigms. The first initiates iNexin administration concurrent with the onset of hyperglycemia; the second initiates treatment at the clinical manifestation of retinal vascular abnormalities. We will also confirm aCT1 biodistribution in the diabetic eye following topical ocular administration and aCT1’s localization to retinal epithelial and endothelial cells. Successful completion of these activities will provide proof-of-concept efficacy for aCT1’s mechanism of action translating to therapeutic effectiveness in the treatment of DR, while also supporting project advancement into efficacy and safety studies in large (non-rodent) animal models of DR. Translation into the clinic will mean significantly improved outcomes for the >8M diabetic adults in the US alone.

糖尿病视网膜病变（DR）是美国成年人失明和视力障碍的主要原因。 DR 的护理标准是玻璃体内 (IVT) 注射抗血管内皮生长因子 (VEGF) 抑制血管通透性和新生血管形成的治疗方法然而，抗VEGF药物的作用有限。 IVT 注射的侵入性也与较差的疗效相关。依从性以及严重的副作用因此，对创新的医疗需求尚未得到满足。有效减轻 DR 发病机制和进展的无创治疗。我们建议评估含肽滴眼剂配方 (iNexin™) 的治疗潜力通过保持血视网膜屏障 (BRB) 的完整性来缓解 DR 病理生理学。视网膜血管内皮细胞和视网膜色素上皮细胞的紧密连接在 DR 早期就破裂发病机制并导致血管通透性和渗漏以及炎症，导致视网膜丧失体内平衡和神经退行性变也会破坏细胞间的间隙连接。因此，保护细胞间连接具有重要意义。 Connexin43 (Cx43) 是细胞间质的跨膜蛋白成分。连接对屏障功能完整性、细胞间通讯和细胞凋亡至关重要。 Research Inc. 开发了 Cx43 的治疗性肽模拟物、α-连接蛋白羧基末端 (aCT1)、稳定细胞间连接，同时调节半通道活性以保持屏障功能，减少 iNexin 是一种稳定的非甾体、不含防腐剂的 aCT1 滴眼液。经过一系列全面的安全性和有效性研究验证的配方。 iNexin 治疗将稳定包含 BRB 的细胞间连接，从而改善 DR 病理生理学，为了验证这一假设，我们建议进行概念验证。 iNexin 减轻糖尿病视网膜病变（目标 1）的功效，并确认 aCT1 在糖尿病眼中的生物分布滴眼剂给药后（目标 2）使用翻译相关的链脲佐菌素诱导的 1 型糖尿病。大鼠模型中，我们建议使用两种不同的治疗范例来评估 iNexin 对 DR 的影响。在高血糖发作的同时开始 iNexin 给药；第二个在我们还将确认糖尿病患者视网膜血管异常的临床表现。局部眼部给药和 aCT1 定位至视网膜上皮和内皮细胞后的眼睛。这些活动的成功完成将为 aCT1 的作用机制提供概念验证功效转化为 DR 治疗的疗效，同时也支持项目进展 DR 大型（非啮齿类）动物模型的功效和安全性研究将意味着转化为临床。仅在美国，就显着改善了超过 800 万糖尿病成人的预后。