Evaluation of a Connexin-based Peptide for the Treatment of Age-Related Macular Degeneration

项目摘要/摘要： FirstStringResearch发现了一种新的多肽，它在治疗AGE方面具有治疗潜力-- 相关性黄斑变性(AMD)。本第一阶段SBIR将评估以下两个方面的可行性和机制 用于治疗AMD的基于连接蛋白的人工合成多肽ACT1的局部给药。 AMD是一种视网膜疾病，患者通过病理和病理改变而逐渐丧失中心视力 黄斑损伤情况与血管内皮生长因子介导的脉络膜新生血管的形成 (CNV)。以血管内皮生长因子为靶点的已获批准的治疗药物是首选的治疗方案，但需要 慢性高侵入性玻璃体内注射，有安全问题，效果不是很好。一个有效的， 治疗AMD的安全、局部配方代表着一项重大且亟需的创新。 Act1是一种基于连接蛋白43 C-末端序列的小分子可溶性多肽，其工程直接作用于 转移到细胞内，而不需要任何可能有毒的化合物作为局部或细胞内药物 送货。当局部应用于皮肤伤口时，Act1安全地促进愈合，减少炎症和 形成疤痕，并促进复杂的组织再生。Act1肽在皮肤创面愈合中的独特作用 和组织再生，结合AMD的非血管成分对应于 黄斑下伤口愈合或组织修复反应提示有治疗机会 AMD。初步研究表明，局部使用Act1滴眼液可降低CNV和 稳定小鼠视网膜色素上皮(RPE)屏障功能 病理生理学AMD。这项建议的目标是评估治疗潜力和机制。 Act1多肽在滴眼液配方中的作用，作为一种新的微创疗法，以防止 AMD的进展和视网膜功能的恢复。为了实现这一目标，FirstString Research将：1. 进一步阐明ACT1‘S保护RPE屏障功能的治疗潜力和作用机制 用AMD小鼠模型抑制CNV；Act1可能通过减少Cx43而减轻炎症 半通道活动和稳定紧密连接的完整性。实验将包括对势能的研究 ACT1和抗血管内皮生长因子治疗药物之间的协同作用。2.)确定Act1可通过以下方式传递的剂量 滴眼液在兔CNV模型中取得疗效，并检查未受伤眼睛的潜在副作用。 这些目标的完成将提供足够的数据来证明治疗的潜力和机制。 Act1在稳定RPE网络中的作用，以支持配方优化，并进一步 在第二阶段提案中对其他大型动物的疗效和PK/毒性研究进行验证。

PROJECT SUMMARY/ABSTRACT: FirstString Research has identified a novel peptide that shows therapeutic potential in the treatment of age- related macular degeneration (AMD). This Phase I SBIR will assess both the feasibility and mechanism of action involved in the topical delivery of a synthetic connexin-based peptide, aCT1, for the treatment of AMD. AMD is a retinal disease in patients who progressively lose their central vision through pathological and damaging conditions of the macula and the development of VEGF-mediated choroidal neovascularization (CNV). Approved therapeutics that target VEGF are the therapeutic option of choice but are costly, require chronic highly invasive intravitreal injections, have safety concerns and are modestly effective. An effective, safe, topical formulation for the treatment of AMD represents a significant and much needed innovation. aCT1 is a small, soluble peptide based on the C-terminal sequence of connexin43, engineered to directly translocate into cells without the requirement of any potentially toxic compound for topical or intracellular drug delivery. When applied topically on skin wounds aCT1 safely promotes healing, reduces inflammation and scarring, and promotes complex tissue regeneration. aCT1 peptide's unique properties in skin wound healing and tissue regeneration combined with evidence that the non-vascular components of AMD correspond to a submacular wound healing or tissue repair response suggest therapeutic opportunity in the treatment of AMD. Preliminary studies show that topical application of an aCT1 eyedrop formulation reduces CNV and stabilizes the barrier function of the retinal pigment epithelium (RPE) in mouse models mimicking the pathophysiology AMD. The goal of this proposal is to evaluate the therapeutic potential and mechanism of action of the aCT1 peptide in an eye drop formulation, as a novel minimally invasive therapy, to prevent the progression of AMD and restore retinal function. To accomplish this goal, FirstString Research will: 1.) Further delineate aCT1's therapeutic potential and mechanism of action in preserving RPE barrier function and inhibiting CNV using mouse models of AMD; where aCT1 might reduce inflammation by reducing Cx43 hemichannel activity and stabilize tight junction integrity. Experiments will include the investigation of potential synergy between aCT1 and anti-VEGF therapeutics. 2.) Identify the dose in which aCT1 can be delivered by eye-drops to achieve efficacy in a rabbit model of CNV and examine potential side effects in uninjured eyes. The completion of these aims will provide sufficient data to demonstrate therapeutic potential and mechanism of action of aCT1 in stabilizing the RPE network in order to support formulation optimization and further validation in additional large animal efficacy and PK/toxicity studies in a Phase 2 proposal.