Determining Effectiveness of V-10 Self-Assembling Pro-Angiogenic Peptide in Re-Vascularizing and Accelerating Wound-Healing in a BBZDR Rat Model of Diabetic Foot Ulceration

确定 V-10 自组装促血管生成肽在 BBZDR 糖尿病足溃疡模型大鼠血管重建和加速伤口愈合中的有效性

基本信息

  • 批准号:
    10018641
  • 负责人:
  • 金额:
    $ 10.9万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-09-15 至 2020-12-19
  • 项目状态:
    已结题

项目摘要

Project Summary / Abstract NangioTx has developed a patented technology for promoting neovascularization in ischemic tissues. Its lead compound is a 33-amino-acid pro-angiogenic peptide V-10, which, when injected into an ischemic tissue microenvironment, generates mature microvasculature, aiding tissue regeneration. A proof of concept for such tissue regeneration has been obtained in a murine hind-limb ischemia model. The FDA has informed us that this proof of concept is sufficient for NangioTx to test the compound in humans provided that we document that no toxic or undesirable side effects are associated with our peptide. The company is now conducting formal safety and toxicity studies to support a future IND application. We have selected Diabetic Foot Ulcers (DFU) as our initial therapeutic target. DFU is a serious complication in >23 million diabetics in the U.S., doubling the cost of care per patient. Each diabetic is likely to develop at least one diabetic ulcer during the course of the disease. Lesions of this type can enlarge quickly, become infected and require radical clinical intervention including limb amputation. Conventional management of DFU involves frequent visits to physician offices while the more advanced/expensive treatments are not generally effective, leaving the patient to endure a chronic health condition. The processes associated with the development of DFU involve dysfunction in many elements of normal wound healing mechanisms, such as the poor production of blood-vessel networks needed for wound resolution. We hypothesize that our pro-angiogenic peptide scaffold will initiate development of new mature blood vessels in the DFU tissue, facilitating wound healing could proceed. In this SBIR grant application, we aim to determine the efficacy of this material to generate new blood vessels in a established and validated diabetic rat model of chronic, slow-healing wounds. A total of 40 inbred Bio-Breeding Zucker diabetic rats will be randomized into five experimental groups each comprised of 8 animals. Wounds will be treated by the application of V-10 hydrogel or vehicle as follows: Group A will receive a topical application of 25 µL V-10; Group B will be treated with an equal volume of vehicle; Group C will receive 25 µL of V-10 hydrogel by intramuscular injection; Group D will receive 50 µL V-10 hydrogel by intramuscular injection; and Group E will serve as the vehicle control for the injected groups. Tissue samples collected from the animals after 30 days of treatment will be examined by histopathology for parameters of inflammation, granulation, and re- epithelialization. Fibrous connective tissue in the granulation bed will be quantified using a computerized image- analysis system. In parallel, storage stability of V-10 and its formulation will be monitored throughout the duration of the study using mass spectrometry. Any detected degradation product at level of >1% will be characterized. Success in this project would increase the confidence of potential investors in NangioTx regenerative technology; it would accelerate our preclinical and translational efforts by attracting funding to complete studies necessary for a successful IND application, thus enabling our company to develop a new therapy that would fill a significant unmet medical need in DFU.
项目总结/摘要 NangioTx开发了一种专利技术,用于促进缺血组织中的新血管形成。其领先优势 化合物是33个氨基酸的促血管生成肽V-10,当注射到缺血组织中时, 微环境,产生成熟的微血管,帮助组织再生。这种概念的证明 在小鼠后肢缺血模型中已经获得了组织再生。FDA已经通知我们, 概念证明足以让NangioTx在人体中测试该化合物,前提是我们证明没有 毒性或不希望的副作用与我们的肽有关。该公司现在正在进行正式的安全 和毒性研究,以支持未来的IND申请。 我们选择糖尿病足溃疡(DFU)作为我们的初始治疗目标。DFU是严重的并发症, 美国有超过2300万糖尿病患者,使每位患者的医疗成本翻倍。每一个糖尿病患者都可能至少 一个糖尿病溃疡在疾病的过程中。这种类型的病变可以迅速扩大,成为感染 并且需要包括截肢的彻底临床干预。DFU的常规管理包括 频繁访问医生办公室而更先进/昂贵的治疗通常不是有效的, 使患者忍受慢性健康状况。与DFU开发相关的过程 涉及正常伤口愈合机制的许多要素的功能障碍,例如 伤口愈合所需的血管网络我们假设我们的促血管生成肽支架 将启动DFU组织中新的成熟血管的发育,促进伤口愈合。 在这项SBIR资助申请中,我们的目标是确定这种材料在体内生成新血管的功效。 一种建立并验证的慢性、缓慢愈合伤口的糖尿病大鼠模型。共40个近交系生物育种 将Zucker糖尿病大鼠随机分为5个实验组,每组8只动物。伤口会 通过如下施用V-10水凝胶或载体进行治疗:A组将接受局部施用 25 µL V-10; B组将接受等体积的溶剂处理; C组将接受25 µL V-10水凝胶 D组将通过肌内注射接受50 µL V-10水凝胶; E组将通过肌内注射接受50 µL V-10水凝胶; 作为注射组的溶媒对照。30天后从动物中采集的组织样品 治疗将通过组织病理学检查炎症、肉芽形成和再狭窄的参数。 上皮化将使用计算机图像对肉芽床中的纤维结缔组织进行定量- 分析系统同时,将在整个期间监测V-10及其制剂的储存稳定性 使用质谱分析法进行研究。将对任何检测到的水平>1%的降解产物进行表征。 该项目的成功将增加潜在投资者对NangioTx再生技术的信心; 它将通过吸引资金来完成必要的研究, 成功的IND申请,从而使我们公司能够开发一种新的治疗方法, DFU中未满足的医疗需求。

项目成果

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