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.

项目概要/摘要 NangioTx 开发了一项促进缺血组织新生血管形成的专利技术。 该化合物是一种 33 个氨基酸的促血管生成肽 V-10，当注射到缺血组织时 微环境，产生成熟的微血管，帮助组织再生。 FDA 已在小鼠后肢缺血模型中实现了组织再生。 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 有毒或不良副作用与我们的肽有关，该公司目前正在进行正式的安全检查。 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 是一种严重的并发症。 美国有超过 2300 万糖尿病患者，每位患者的护理费用可能至少增加一倍。 糖尿病性溃疡在病程中会迅速扩大、感染。 并需要根治性临床干预，包括 DFU 的常规治疗。 经常去医生办公室，而更先进/昂贵的治疗方法通常并不有效， 让患者忍受与 DFU 发展相关的慢性健康状况。 涉及正常伤口愈合机制的许多要素的功能障碍，例如生产不良 我们采用了促血管生成肽支架。 将启动 DFU 组织中新的成熟血管的发育，促进伤口愈合。 在此 SBIR 拨款申请中，我们的目标是确定该材料在以下部位生成新血管的功效： 已建立并经过验证的慢性伤口愈合缓慢的糖尿病大鼠模型 总共 40 只近交生物繁殖。 Zucker 糖尿病大鼠将被随机分为 5 个实验组，每组由 8 只动物组成。 通过使用 V-10 水凝胶或赋形剂进行治疗，如下所示：A 组将接受局部应用 25 µL V-10；B 组将使用等体积的载体进行处理；C 组将接受 25 µL V-10 水凝胶。 通过肌肉注射；D组将通过肌肉注射接受50 µL V-10水凝胶； 作为注射组30天后收集的组织样本的载体对照。 治疗将通过组织病理学检查炎症、肉芽形成和再治疗的参数。 肉芽床上的纤维结缔组织将使用计算机图像进行量化。 同时，V-10 及其配方的储存稳定性将在整个过程中受到监控。 任何检测到的>1% 水平的降解产物都将被表征。 该项目的成功将增强潜在投资者对 NangioTx 再生技术的信心； 它将通过吸引资金完成必要的研究来加速我们的临床前和转化工作 成功的 IND 申请，从而使我们公司能够开发出一种新的疗法，该疗法将填补重要的空白 DFU 中未满足的医疗需求。