Multivalent Conjugates of Sonic Hedgehog to Accelerate Diabetic Wound Healing

2012年，近100万美国糖尿病患者被诊断患有下肢溃疡，这些伤口未能愈合导致超过75,000例下肢截肢。Valitor公司正在开发蛋白质聚合物疗法，以克服糖尿病伤口愈合的微血管后果。我们设计了我们的治疗方法，以补充糖尿病溃疡管理的标准实践，并减少了对这些缓慢愈合的伤口进行清创和临床观察所需的昂贵的一系列努力。我们的专利技术是一种生物偶联过程，使我们能够将Sonic hedgehog (Shh)（一种重要的血管生成因子）以确定的Shh:HyA比率（即价）连接到透明质酸（HyA）的线性链上。在该项目的第一阶段，我们验证了Shh价与Shh诱导的细胞功能增强相关，包括下游血管生成信号，相对于等摩尔浓度的未共轭Shh，这些功能基本上不受调节。我们进一步证明，在用多价Shh偶联物（mvShh）治疗后，db/db糖尿病小鼠的全层切除伤口与未偶联Shh或载体对照治疗的伤口相比，表现出更大的新血管密度和更快的愈合时间。我们在II期的总体目标是通过完成先导优化过程，在这些有希望的机制验证结果的基础上，推进mvShh作为临床前研究的候选药物。

DESCRIPTION: In 2012, nearly one million Americans with diabetes were diagnosed with a lower extremity ulcer, and failure of these wounds to heal resulted in more than 75,000 lower extremity amputations. Valitor, Inc. is developing protein-polymer therapeutics to overcome the micro vascular consequences of diabetic wound healing. We designed our therapy to complement the standard practice of diabetic ulcer management and to reduce the costly serial effort required for debridement and clinical observation of these slowly healing wounds. Our patented technology is a bio conjugation process that enables us tether Sonic hedgehog (Shh), an important angiogenic factor, to linear chains of hyaluronic acid (HyA) at defined Shh:HyA ratios (i.e., valency). In Phase I of this project, we verified that Shh valency correlated with enhanced Shh-induced cellular functions, including downstream angiogenic signaling, which were substantially unregulated relative to equimolar concentrations of unconjugated Shh. We further demonstrated that after treatment with multivalent Shh conjugates (mvShh), full- thickness excisional wounds in db/db diabetic mice exhibited significantly greater neovascular density and faster closure times compared to wounds treated with unconjugated Shh or vehicle controls. Our overall goal during Phase II is to build on these promising proof-of-mechanism results by completing the lead optimization process and to advance mvShh to as a candidate for pre-clinical studies.