Multivalent Conjugates of Sonic Hedgehog to Accelerate Diabetic Wound Healing

Sonic Hedgehog 的多价结合物可加速糖尿病伤口愈合

基本信息

批准号：
8715296
负责人：
Wesley Michael Jackson
金额：
$ 71.67万
依托单位：
VALITOR, INC.
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-10 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8715296
关键词：
Address Aftercare Alloxan American Amputation Angiogenic Factor Animal Model Architecture Area Becaplermin Beds Biological Availability Biopolymers Blood Circulation Blood Vessels Cell physiology Characteristics Chronic Clinical Clinical Trials Complement Cutaneous Debridement Dermal Diabetes Mellitus Diabetic mouse Diabetic ulcer Diabetic wound Diagnosis Drug or chemical Tissue Distribution Ear Endothelial Cells Enzyme-Linked Immunosorbent Assay Erinaceidae Exhibits FDA approved Failure Family suidae Fibroblasts Goals Growth Factor Healed Health Care Costs Healthcare Histology Human Hyaluronic Acid Immunohistochemistry Impairment Infection Investigational Drugs Ischemia Lead Leg Ulcer Legal patent Lower Extremity Marketing Measures Mechanics Modeling Molecular Operative Surgical Procedures Oryctolagus cuniculus Outcome Patients Performance Pharmaceutical Preparations Pharmacotherapy Phase Phenotype Platelet-Derived Growth Factor Polymers Preclinical Testing Process Proteins Protocols documentation Recombinants Relative (related person)Risk Role Route Signal Transduction Sonic Hedgehog Pathway Sonic hedgehog protein Streptozocin Technology Testing Therapeutic Therapeutic Effect Thick Time Tissues Translations Treatment Cost Validation Vascular blood supply Wound Healing cohort commercialization cost db/db mouse density design diabetic diabetic wound healing healing improved mouse model neovascular neovascularization non-diabetic preclinical study process optimization public health relevance research study response standard of care treatment effect wound

项目摘要

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.

描述：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, Inc. 正在开发蛋白质聚合物疗法，以克服糖尿病伤口愈合对微血管的影响。我们设计的治疗方法是为了补充糖尿病溃疡治疗的标准实践，并减少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连续工作。我们的专利技术是一种生物缀合工艺，使我们能够以规定的 Shh:HyA 比率（即化合价）将重要的血管生成因子 Sonic hedgehog (Shh) 与透明质酸 (HyA) 线性链连接。在该项目的第一阶段，我们验证了Shh价与增强的Shh诱导的细胞功能相关，包括下游血管生成信号，相对于等摩尔浓度的未结合的Shh来说，这些信号基本上不受调节。我们进一步证明，在用多价Shh缀合物（mvShh）治疗后，与用未缀合的Shh或媒介物对照治疗的伤口相比，db/db糖尿病小鼠的全层切除伤口表现出显着更高的新生血管密度和更快的闭合时间。我们在第二阶段的总体目标是通过完成先导优化过程来建立这些有希望的机制证明结果，并将 mvShh 提升为临床前研究的候选者。