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

基于连接蛋白的肽治疗年龄相关性黄斑变性的评价

• 批准号: 9346869
• 负责人: Gautam Sudhir Ghatnekar
• 金额: $ 22.5万
• 依托单位: XEQUEL BIO, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9346869
• 关键词: Acute; Adverse effects; Affect; Age related macular degeneration; American; Animal Model; Atrophic; Blindness; Blocking Antibodies; Blood; Bruch' s basal membrane structure; C-terminal; Calcium; Cells; Choroid; Choroidal Neovascularization; Chronic; Cicatrix; Complex; Connexin 43; Connexins; Data; Deposition; Deterioration; Development; Diffuse; Disease; Disease Progression; Dose; Drug Delivery Systems; Engineering; Epithelium; Evaluation; Excipients; Extravasation; Eye; Eye diseases; Eyedrops; Formulation; Functional disorder; Generations; Goals; Growth; Health; In Vitro; Inflammation; Injury; Investigation; Lasers; Lead; Leg Ulcer; Light; Mediating; Modeling; Mus; Operative Surgical Procedures; Oryctolagus cuniculus; Pathologic; Pathology; Patients; Peptides; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Photoreceptors; Poison; Prevalence; Property; Refractory; Research; Retina; Retinal; Retinal Diseases; Safety; Skin wound; Small Business Innovation Research Grant; Structure of retinal pigment epithelium; Therapeutic; Tight Junctions; Time; Tissues; Topical application; Toxic effect; Treatment Efficacy; VEGFA gene; Validation; Vascular Endothelial Growth Factors; Venous; Vision; Wound Healing; animal efficacy; base; chelation; clinical development; combat; combinatorial; cost; diabetic; effective therapy; experimental study; extracellular; geographic atrophy; healing; improved; in vivo; innovation; intravitreal injection; macula; minimally invasive; monolayer; mouse model; novel; prevent; response; synergism; therapeutic development; therapeutic target; tissue regeneration; tissue repair

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.

项目总结/摘要： FirstString Research发现了一种新的肽，它在治疗衰老方面显示出治疗潜力。 相关性黄斑变性（AMD）。第一阶段SBIR将评估以下内容的可行性和机制 涉及局部递送合成的基于连接蛋白的肽aCT 1以治疗AMD的作用。 AMD是一种视网膜疾病，患者通过病理性和非病理性视网膜病变逐渐丧失其中心视力， 黄斑的损伤条件和VEGF介导的脉络膜新生血管的发展 （CNV）。批准的靶向VEGF的治疗剂是治疗选择，但昂贵，需要 慢性高度侵入性玻璃体内注射具有安全性问题并且是适度有效的。一个有效的， 用于治疗AMD的安全的局部制剂代表了重要的和急需的创新。 aCT 1是一种基于连接蛋白43的C-末端序列的小的可溶性肽，经工程改造以直接与细胞连接。 不需要任何潜在毒性化合物的局部或细胞内药物 交付.当局部应用于皮肤伤口时，aCT 1安全地促进愈合，减少炎症， 疤痕，并促进复杂的组织再生。aCT 1肽在皮肤创伤愈合中的独特性质 和组织再生结合证据表明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治疗机会 AMD.初步研究表明，局部应用aCT 1滴眼液制剂可减少CNV， 稳定模拟视网膜色素上皮细胞（RPE）的小鼠模型中的屏障功能。 病理生理学本提案的目的是评估的治疗潜力和机制 aCT 1肽在滴眼剂制剂中的作用，作为一种新的微创疗法， AMD的进展和恢复视网膜功能。为了实现这一目标，FirstString Research将：1。 进一步阐明aCT 1在保护RPE屏障功能方面的治疗潜力和作用机制 和使用AMD小鼠模型抑制CNV;其中aCT 1可通过减少Cx43来减少炎症 半通道活性和稳定紧密连接完整性。实验将包括潜在的调查 aCT 1和抗VEGF治疗剂之间的协同作用。2.）的情况。通过以下方式确定可输送aCT 1的剂量： 滴眼液以在CNV的兔模型中实现功效，并检查未受伤眼睛中的潜在副作用。 这些目标的完成将为证明治疗潜力和机制提供足够的数据 aCT 1在稳定RPE网络中的作用，以支持制剂优化，并进一步 在II期提案中的其他大型动物疗效和PK/毒性研究中进行验证。