A novel PEDF peptide mimetic for diabetic retinopathy

一种治疗糖尿病视网膜病变的新型 PEDF 肽模拟物

基本信息

批准号：
10680606
负责人：
Ji-Ye Wei
金额：
$ 53.75万
依托单位：
SKYRAN BIOLOGICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10680606
关键词：
Acute Address Adoption Aftercare Amino Acids Animals Artificial Tears Back Biological Assay Biological Availability Biological Products Biomimetics Blindness Blood Vessels C-terminal Cataract Cell Death Chemicals Clinical Clinical Trials Complications of Diabetes Mellitus Cornea Development Diabetic Nephropathy Diabetic Retinopathy Disease Dose Eye Eye diseases Eyedrops Formulation Frequencies Gender Genetic Glycoproteins Goals Human In Vitro Inflammation Label Lead Legal patent Length MAP Kinase Gene Marketing Modeling Modification Oryctolagus cuniculus Outcome Pathology Pathway interactions Penetration Peptides Phase Phase I Clinical Trials Phase II Clinical Trials Phylogenetic Analysis Population Positioning Attribute Proteins Reproducibility Research Retina Retinal Degeneration Rodent Safety Series Small Business Technology Transfer Research Structure Symptoms Temperature Testing Therapeutic Tissues Toxic effect Treatment Efficacy Vascular Endothelial Growth Factors Vision Visual Visual Acuity Work alpha helix analog chemical synthesis clinical development clinical translation clinically relevant commercial application cost cost effective treatment diabetic dosage drug efficacy improved in vivo in vivo Model injured lead candidate mimetics molecular modeling mouse model neuroprotection novel novel therapeutics peptide analog peptidomimetics phase 1 study phase 2 study pigment epithelium-derived factor pigment epithelium-derived factor receptor pre-Investigational New Drug meeting pre-clinical preclinical study prototype receptor retinal prosthesis retinal toxicity safety assessment systemic toxicity therapeutic protein translational approach

项目摘要

Abstract The overall goal of Skyran Biologics is to develop a potent topical therapeutic for diabetic retinopathy (DR), a leading cause of vision loss globally. Our research team identified Pigment Epithelium-Derived Factor (PEDF) and showed it is expressed in the eye and provides significant protection to the injured retina. Since its discovery, we identified a 44-mer N-terminus bioactive region of PEDF, then generated over 40 structurally different analogs to this region. We screened these mimetics for biological activity in a set of rigorous in vitro and in vivo assays for DR and identified Spx81-5 as a lead small PEDF mimetic with improved bioactivity in the DR retina over the native 44-mer fragment. A chemically and reproducibly synthesized small bioactive peptide removes some of the therapeutic challenges and cost encountered with a large glycoprotein in treating ocular diseases. STTR Phase I Preclinical Summary: We extended previous studies showing that Spx81-5 reduces inflammation, vascular pathologies, and cell death in DR to now show that topical instillations of Spx81-5 effectively improves visual acuity and contrast thresholds in diabetic rodents, activates MAPK through the ATGL receptor, and is detected at therapeutic concentrations after a single low dose in rabbit retinas where there is substantial back-to-front vitreal flow. We also show that Spx81-5 is stable at various temperatures for >5 months and that a novel formulation FLP3 delivers ~70% more Spx81-5 to the retina than artificial tears. Pre-clinical Phase II study: We propose to continue to develop Spx81-5 for DR and will use three aims to address key scientific issues essential for filing an IND application: The first is to establish Dosage and Instillation Frequency of Spx81-5 in a novel eye drop Formulation (FLP3) to achieve maximal therapeutic benefits in a genetic mouse model (Ins2Akita) of DR. The second is to validate Bioavailability (PK) and Efficacy of Spx81- 5/FLP3 in Larger Rabbit Eyes with DR, and the third is to assess Safety and Tolerability of Spx81-5/FLP3 in rabbit ocular and non-ocular tissues to allow prediction for human treatment. Commercial Potential: Skyran Biologics Inc. can significantly increase clinical value of Spx81-5 by definitively demonstrating that (i) the improved FLP3 topical vehicle enhances posterior segment delivery of the peptide, (ii) topical instillations of Spx81-5/FLP3 restores visual function across multiple models of DR, and (iii) the peptide is safe and tolerated in large animals. These studies are critical and essential to support the current regulatory paradigm and to inform a pathway to human trials. The milestones achieved by the successful completion of this work will position us to propose development of GMP grade peptide and formulation for clinical translation. The Phase II work will move us towards essential IND-enabling studies for FDA approval and development of clinical phase translational strategies.

抽象的 Skyran Biologics 的总体目标是开发一种有效的糖尿病视网膜病变 (DR) 局部治疗药物，全球视力丧失的主要原因。我们的研究团队发现了色素上皮衍生因子 (PEDF) 并表明它在眼睛中表达并为受伤的视网膜提供重要的保护。自从它被发现以来，我们鉴定了 PEDF 的 44 聚体 N 末端生物活性区域，然后生成了 40 多个结构不同的类似物到这个地区。我们通过一系列严格的体外和体内测定筛选了这些模拟物的生物活性并确定 Spx81-5 是一种主要的小 PEDF 模拟物，在 DR 视网膜中具有改善的生物活性天然 44 聚体片段。化学和可重复合成的小生物活性肽去除了一些大糖蛋白在治疗眼部疾病时遇到的治疗挑战和成本。 STTR I 期临床前总结：我们扩展了之前的研究，表明 Spx81-5 减少了 DR 中的炎症、血管病变和细胞死亡现在表明 Spx81-5 的局部滴注有效提高糖尿病啮齿动物的视力和对比度阈值，通过激活 MAPK ATGL 受体，在单次低剂量后在兔视网膜中检测到治疗浓度，其中有大量从后到前的玻璃体血流。我们还表明 Spx81-5 在不同温度下都很稳定超过 5 个月，新型配方 FLP3 向视网膜输送的 Spx81-5 比人工泪液多约 70%。临床前II期研究：我们建议继续开发用于DR的Spx81-5，并将通过三个目标来解决提交 IND 申请所必需的关键科学问题：首先是确定剂量和滴注 Spx81-5 在新型滴眼剂配方 (FLP3) 中的使用频率可在治疗中实现最大治疗效果 DR的遗传小鼠模型（Ins2Akita）。第二个是验证Spx81-的生物利用度（PK）和功效 5/FLP3 在患有 DR 的较大兔眼中的应用，第三个是评估 Spx81-5/FLP3 在 DR 中的安全性和耐受性兔子的眼部和非眼部组织可以预测人类的治疗情况。商业潜力：Skyran Biologics Inc. 可以明确地显着提高 Spx81-5 的临床价值证明 (i) 改进的 FLP3 局部载体增强了肽的后段递送，(ii) Spx81-5/FLP3 的局部滴注可恢复多种 DR 模型的视觉功能，以及 (iii) 肽对于大型动物来说是安全且耐受的。这些研究对于支持当前的监管至关重要且至关重要范式并为人体试验提供途径。成功完成这项工作所取得的里程碑将使我们能够提出开发用于临床转化的 GMP 级肽和制剂。第二阶段的工作将推动我们走向根本 FDA 批准的 IND 支持研究和临床阶段转化策略的开发。