Multivalent Growth Factor Conjugates to Accelerate Wound Neovascularization in El

多价生长因子结合物加速 El 伤口新生血管形成

• 批准号: 8592861
• 负责人: Wesley Michael Jackson
• 金额: $ 31.09万
• 依托单位: VALITOR, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8592861
• 关键词: Acute; Age; American; Angiogenic Factor; Animals; Biopolymers; Biotechnology; Caring; Cells; Chemicals; Chronic; Clinical; Complement; Cutaneous; Data; Dermal; Development; Diffuse; Elderly; Endothelial Cells; Erinaceidae; Event; Expenditure; Failure; Goals; Growth Factor; Harvest; Healed; Hyaluronic Acid; Immunohistochemistry; Impaired wound healing; Impairment; In Vitro; Incidence; Individual; Infection; Injury; Investigational Drugs; Legal patent; Marketing; Measures; Mechanics; Mediating; Mediator of activation protein; Medical; Metabolic Clearance Rate; Modeling; Molecular; Mus; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phenotype; Phosphotransferases; Population; Procedures; Process; Proteins; Proteoglycan; Risk; Rodent; Route; Skin; Specificity; Surgical incisions; Surgical wound; Technology; Tensile Strength; Therapeutic; Thick; Time; Tissues; Translations; Trauma; United States; United States National Institutes of Health; Wound Healing; age group; age related; aged; base; beneficiary; biocompatible polymer; cell motility; commercialization; cost; db/db mouse; design; diabetic; effective therapy; healing; improved; in vitro Assay; in vivo; macromolecule; migration; neovascular; neovascularization; older patient; phase 2 study; pre-clinical; prevent; public health relevance; research study; response; response to injury; smoothened signaling pathway; therapeutic protein; tissue repair; transcription factor; wound

DESCRIPTION: Approximately 4.8 million Americans over the age of 65 currently suffer from age-related wound complications, with an annual expenditure of over $10 billion annually. The elderly are the most likely age group to undergo procedures resulting in surgical wounds, and due to skin changes that occur with advanced age, their skin is also more prone to acute dermal trauma. In addition, delayed cellular events and impaired angiogenic responses to injury increases the time required for these wounds to heal, and in turn, leaves patients more prone to complications such as infection, re-injury and chronic wound development. Valitor, Inc. is developing a protein-based therapy to accelerate neovascularization and improve the rate of wound healing in aged individuals. We designed our therapy to complement the standard practice of wound management and to reduce the costly serial effort required for treatment of these slowly healing wounds. Our patented technology is a chemical tethering process that provides enhanced potency, stability, and specificity of growth factors in vivo. With this technology, we have chemically conjugated Sonic hedgehog (Shh), an important angiogenic factor previously shown to stimulate neovascularization, to linear chains of hyaluronic acid (HyA), a soluble, biocompatible polymer. We can control the valency of growth factors that are delivered to a wound by varying the ratio of Shh:HyA, and we have demonstrated that the Shh valency of our conjugates can modulate their cellular bioactivity. Conjugating Shh to a large macromolecule may also prevent its deactivation by proteolytic enzymes and enhance its molecular stability in the target tissues. In Phase I, our overall goal is to develop mvShh conjugates that improve the mechanisms of wound healing in older individuals by enhancing the migration of endothelial cells (ECs) and accelerating wound neovascularization. In Specific Aim #1 we will develop mvShh conjugates to enhance endothelial cell activation and migration in vitro. In Specific Aim #2 we will evaluate the effect of mvShh on endothelial cell migration and neovascularization in vivo using a full- thickness excisional dermal wound model in 18-month-old mice. The wound size will also be measured periodically until full closure has been achieved. The tensile strength of the repaired tissue will then be evaluated. Our findings will provide valuable proof-of-concept data to guide further pre-clinical development of our drug therapy, which we have planned for Phase II of this project.

描述：目前大约有 480 万 65 岁以上的美国人患有与年龄相关的伤口并发症，每年的支出超过 100 亿美元。老年人是最有可能接受手术造成手术伤口的年龄组，并且由于随着年龄的增长皮肤会发生变化，他们的皮肤也更容易遭受急性真皮创伤。此外，延迟的细胞事件和受损的血管生成反应会增加伤口愈合所需的时间，进而使患者更容易出现感染、再次受伤和慢性伤口发展等并发症。 Valitor, Inc. 正在开发一种基于蛋白质的疗法，以加速老年人的新血管形成并提高伤口愈合率。我们设计的疗法是为了补充伤口处理的标准实践，并减少治疗这些缓慢愈合的伤口所需的昂贵的连续工作。我们的专利技术是一种化学束缚过程，可增强体内生长因子的效力、稳定性和特异性。通过这项技术，我们将 Sonic Hedgehog (Shh)（一种先前被证明可以刺激新血管形成的重要血管生成因子）与透明质酸 (HyA)（一种可溶性生物相容性聚合物）的线性链化学结合。我们可以通过改变Shh:HyA的比例来控制递送到伤口的生长因子的价态，并且我们已经证明我们的缀合物的Shh价态可以调节它们的细胞生物活性。将 Shh 与大分子结合还可以防止其被蛋白水解酶失活，并增强其在靶组织中的分子稳定性。在第一阶段，我们的总体目标是开发 mvShh 结合物，通过增强内皮细胞 (EC) 的迁移和加速伤口新生血管形成来改善老年人的伤口愈合机制。在具体目标#1 中，我们将开发 mvShh 缀合物以增强内皮细胞的体外激活和迁移。在具体目标#2中，我们将使用 18 个月大小鼠的全层切除真皮伤口模型来评估 mvShh 对体内内皮细胞迁移和新生血管形成的影响。还将定期测量伤口大小，直至完全闭合。然后将评估修复组织的拉伸强度。我们的研究结果将提供有价值的概念验证数据，以指导我们药物治疗的进一步临床前开发，我们已计划用于该项目的第二阶段。