A novel PEDF peptide mimetic for diabetic retinopathy

摘要 Skyran Biologics的总体目标是开发一种有效的局部治疗糖尿病视网膜病变(DR)的方法， 全球视力丧失的主要原因。我们的研究小组确定了色素上皮衍生因子(PEDF) 结果表明，它在眼睛中表达，对受损的视网膜提供了显著的保护。自从它被发现以来， 我们鉴定了PEDF的一个44聚体N末端生物活性区域，然后产生了40多个结构不同的类似物 到这个地区。我们在一系列严格的体外和体内试验中筛选了这些模拟物的生物活性。 对于DR，并确定Spx81-5是一种具有改善DR视网膜生物活性的先导小分子PEDF模拟物 天然的44聚体片段。一种化学合成和可重复合成的小生物活性多肽可以去除一些 大糖蛋白在治疗眼部疾病中遇到的治疗挑战和成本。 STTRI期临床前总结：我们扩展了先前的研究，表明Spx81-5可以降低 DR中的炎症、血管病理和细胞死亡现在表明，局部滴注Spx81-5 有效提高糖尿病啮齿动物的视力和对比度阈值，通过 ATGL受体，并在治疗浓度下在兔视网膜中检测到单次低剂量 有大量自后而前的玻璃体血流。我们还表明Spx81-5在不同的温度下都是稳定的 5个月，一种新的配方Flp3比人工泪液多向视网膜输送约70%的Spx81-5。 临床前第二阶段研究：我们建议继续为DR开发Spx81-5，并将使用三个目标来解决 提交IND申请的关键科学问题：第一是确定剂量和滴注 Spx81-5在新型滴眼液配方(FLP3)中的频率，以实现最大的治疗效果 二是验证Spx81的生物利用度(PK)和疗效。 SPX81-5/FLP3在糖尿病视网膜病变中的安全性和耐受性 兔眼和非眼组织，以允许预测人类的治疗。 商业潜力：Skyran Biologics Inc.可以显著提高Spx81-5的临床价值 证明(I)改进的Flp3局部载体增强了多肽的后段递送，(Ii) 局部滴注Spx81-5/Flp3可恢复多种模型DR的视觉功能，以及(Iii)该肽 在大型动物身上是安全和耐受的。这些研究对支持当前的监管是至关重要的 并为人体试验提供了一条途径。 这项工作的成功完成所取得的里程碑将使我们能够建议发展 临床翻译用GMP级多肽及其制剂。第二阶段的工作将把我们推向基本 支持IND的研究，以获得FDA的批准，并开发临床阶段转换策略。

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.