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

• 批准号: 10018641
• 负责人: Marwa Choudhury
• 金额: $ 10.9万
• 依托单位: NANGIOTX, INC.
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10018641
• 关键词: Acetylation; Amides; Amino Acids; Amputation; Angiogenic Peptides; Animals; Applications Grants; Beds; Biocompatible Materials; Blood Vessels; Breeding; Cell physiology; Chronic; Clinic; Clinical; Complex; Complication; Connective Tissue; Coupling; Cytoplasmic Granules; Development; Diabetic Foot Ulcer; Dialysis procedure; Disease; Dorsal; Effectiveness; Electrons; Elements; Epithelial; Epithelium; Formulation; Foundations; Freeze Drying; Functional disorder; Funding; Future; Goals; Granulation Tissue; Growth Factor; Health; Healthcare Systems; Heterogeneity; Hindlimb; Histopathology; Human; Hydrogels; Image; In Vitro; Inbreeding; Income; Inflammation; Injections; Intervention; Intramuscular Injections; Ischemia; Knowledge; Lead; Legal patent; Lesion; Limb structure; Lower Extremity; Mass Spectrum Analysis; Medical; Methodology; Modeling; Molecular Weight; Monitor; Mus; N-terminal; Obesity; Operative Surgical Procedures; Outpatients; Pathologic Processes; Patients; Peptide Synthesis; Peptides; Pharmaceutical Preparations; Phase; Physicians' Offices; Plant Resins; Process; Production; Productivity; Property; Publishing; Punch Biopsy; Quality of life; Randomized; Rattus; Reagent; Recovery; Safety; Sampling; Side; Skin; Small Business Innovation Research Grant; Sodium Chloride; Solid; Source; Sterility; Sucrose; System; Systems Analysis; Technology; Temperature; Testing; Therapeutic Effect; Tissue Sample; Tissues; Topical application; Toxic effect; Translations; Visit; Water; Wound models; base; care costs; chronic ulcer; chronic wound; computerized; design; diabetes management; diabetic; diabetic rat; diabetic ulcer; experimental group; foot; healing; histopathological examination; imaging software; instrument; ionization; limb amputation; mouse model; neovascularization; non-healing wounds; novel therapeutics; peptide V; pre-clinical; regenerative; scaffold; self assembly; side effect; small molecule; success; therapeutic angiogenesis; therapeutic target; tissue regeneration; treatment duration; wound; wound healing

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.

项目摘要 /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。它的领导 化合物是一种33-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脉管系统，有助于组织再生。这样的概念证明 在鼠后中性缺血模型中已获得组织再生。 FDA告诉我们这 概念验证足以让Nangiotx测试人类中的化合物，只要我们没有证明 有毒或不良的副作用与我们的肽有关。该公司现在正在进行正式安全 和毒性研究以支持未来的IND应用。 我们选择了糖尿病足溃疡（DFU）作为我们最初的治疗靶点。 DFU是严重的并发症 在美国> 2300万糖尿病患者，每位患者的护理费用翻了一番。每个糖尿病患者至少可能发展 疾病过程中一种糖尿病性溃疡。这种类型的病变会迅速扩大，被感染 并需要根治性的临床干预措施，包括肢体截肢。 DFU的常规管理涉及 经常访问实体办公室，而更高级/昂贵的治疗通常不有效， 让患者忍受慢性健康状况。与DFU的发展相关的过程 在正常伤口愈合机制的许多元素中涉及功能障碍，例如生产不良 解决伤口所需的血管网络。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展，可以支撑增益愈合。 在此SBIR赠款的应用中，我们旨在确定该材料的效率，以生成新的血管 慢性，缓慢的奖金的已建立且经过验证的糖尿病大鼠模型。共有40个近交的生物繁殖 扎克糖尿病大鼠将被随机分为五个实验组，分别由8只动物组成。伤口会 通过使用V-10水凝胶或车辆的应用如下：A组将收到一个局部应用 25 µL V-10; B组将用相等的车辆处理； C组将接收25 µL的V-10水凝胶 通过肌内注射； D组将通过肌内注射接受50 µL V-10水凝胶； E组将 充当注射组的车辆控制。 30天后从动物中收集的组织样品 治疗将通过组织病理学检查，以了解炎症，肉芽和重新的参数 上皮化。肉芽床中的纤维结缔组织将使用计算机图像进行定量 - 分析系统。同时，将在整个持续时间内监视V-10及其公式的存储稳定性 研究使用质谱法。任何检测到的降解产物以> 1％的含量为特征。 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来加速我们的临床前和翻译工作 对于成功的IND应用程序，使我们的公司能够开发一种新的疗法，以填补重要的 DFU未满足的医疗需求。