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

• 批准号: 8843788
• 负责人: Wesley Michael Jackson
• 金额: $ 78.29万
• 依托单位: VALITOR, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-10 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8843788
• 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; 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; research study; response; standard of care; treatment effect; wound

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.

产品说明：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，并减少清创和临床观察这些缓慢愈合的伤口所需的昂贵的连续努力。我们的专利技术是一种生物缀合过程，使我们能够将重要的血管生成因子Sonic hedgehog（Shh）以规定的Shh：HyA比例（即，化合价）。在该项目的第一阶段，我们验证了Shh化合价与增强的Shh诱导的细胞功能相关，包括下游血管生成信号传导，其相对于等摩尔浓度的未缀合的Shh基本上不受调节。我们进一步证明，在用多价Shh缀合物（mvShh）处理后，db/db糖尿病小鼠中的全层切除伤口与用未缀合的Shh或载体对照处理的伤口相比表现出显著更大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电极导线优化过程，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。