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

• 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
• 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

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损害的主要原因。当前 DR标准治疗是玻璃体内（IVT）注射抗血管内皮生长因子（VEGF） 抑制血管渗透性和新血管形成的治疗剂。然而，抗VEGF药物具有有限的 在相当大比例的DR患者中有效。IVT注射的侵入性也与不良的 以及严重的副作用。因此，存在对创新药物的未满足的医疗需求。 有效缓解DR发病机制和进展的非侵入性治疗。在这个研究应用中， 我们建议评估含肽滴眼液制剂（iNexin™）的治疗潜力， 通过保持血-视网膜屏障（BRB）的完整性减轻DR病理生理学。BRB由以下人员组成 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早期就被破坏 发病机制，并导致血管通透性和渗漏以及炎症，导致视网膜功能丧失， 稳态和神经变性。糖尿病相关因素也破坏细胞间的间隙连接 因此，保护细胞间连接是一个重要的 连接蛋白43（Cx43）是一种跨膜蛋白组分，其在DR的治疗中起重要作用。 连接，有助于屏障功能的完整性，细胞-细胞通信和凋亡。FirstString Research Inc.已经开发了Cx43的治疗肽模拟物，α-连接蛋白羧基末端（aCT 1）， 稳定细胞间连接，同时调节半通道活性以保持屏障功能， 损伤扩散，减少炎症。iNexin是一种稳定的非甾体类、不含类固醇的aCT 1滴眼液 在一系列全面的安全性和有效性研究中验证了该制剂。根据这些研究，我们假设 iNexin治疗将稳定包含BRB的细胞间连接以改善DR病理生理学， 保持视网膜的健康和功能。为了验证这一假设，我们建议展示概念验证 iNexin缓解糖尿病视网膜病变的疗效（目的1），并确认aCT 1在糖尿病眼中的生物分布 滴眼液给药后（目标2）。使用预防相关的链脲佐菌素诱导的1型糖尿病 在大鼠模型中，我们提出使用两种不同的治疗范例来评估iNexin对DR的影响。第一 在高血糖症发作的同时开始iNexin给药;第二个在高血糖症发作时开始治疗。 视网膜血管异常的临床表现。我们还将证实aCT 1在糖尿病患者中的生物分布。 局部眼部给药后的眼部和aCT 1在视网膜上皮和内皮细胞中的定位。 这些活动的成功完成将为aCT 1的作用机制提供概念验证功效 转化为DR治疗的治疗效果，同时也支持项目进展， 在大型（非啮齿类）DR动物模型中进行的有效性和安全性研究。 仅在美国就显著改善了> 800万糖尿病成人的结局。