Improve Wound Healing with HIF-CA5 DNA Vector and Electroporation

利用 HIF-CA5 DNA 载体和电穿孔改善伤口愈合

基本信息

批准号：
7860120
负责人：
John W Harmon
金额：
$ 17.31万
依托单位：
CANTON BIOTECHNOLOGIES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-27 至 2012-08-26
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7860120
关键词：
Agreement Amputation Angiogenic Peptides Angiopoietin-1 Angiopoietin-2 Animals Biodistribution Biological Assay Biotechnology Clinic Clinical Clinical Data Clinical assessments Computer Assisted Control Groups DNA DNA delivery Databases Development Devices Diabetes Mellitus Diabetic mouse Dose Effectiveness Electroporation Evaluation Feedback Foot Ulcer Foundations Healed Health Status Histologic Human Human Resources Hypoxia Inducible Factor Impaired wound healing Individual Kinetics Letters Licensing Lower Extremity Mediating Medical Messenger RNA Microscopic Modeling Mus Nature Oxygen Patients Phase Positioning Attribute Procedures Regimen Research Research Personnel Resistance Reverse Transcriptase Polymerase Chain Reaction Risk Safety Secure Site Skin Small Business Technology Transfer Research Specific qualifier value System Technical Expertise Technology Testing Time Tissues Toxic effect Transfection Translations Ulcer United States Universities Up-Regulation Vascular Endothelial Growth Factors Work Wound Healing angiogenesis base diabetic expression vector follow-up foot healing improved mRNA Expression mouse model pre-clinical programs public health relevance research clinical testing response transcription factor vector wound

项目摘要

DESCRIPTION (provided by applicant): Therapy to Improve Wound Healing with DNA Expression Vector for HIF 11 and Electroporation Impaired wound healing is a tremendous problem for individuals with diabetes. Patients with diabetes are at risk for developing foot ulcers. These non-healing ulcerations on the foot are disabling, and their progression leads to amputation of the lower extremity. Diabetes is the most frequent cause for lower extremity amputation in the United States. Based on a decade of research at Johns Hopkins University, Canton Biotechnologies Inc has been created to develop a technology with potential for improving wound healing in diabetic individuals. This technology is based on expressing an oxygen resistant, highly active form of the transcription factor Hypoxia Inducible Factor 11 (CA5-HIF). The approach is based on electroporation (EP) mediated delivery of a DNA expression vector encoding CA5-HIF to the wound. Using a research grade EP device, we have demonstrated sustained expression of HIF after CA5 transfection, resulting in up- regulation of mRNA expression for important angiogenic peptides including VEGF, PLGF, PDGF-B, Angiopoietin 1 and Angiopoietin 2. Pre-clinical testing in diabetic mice with excisional wounds has demonstrated that EP mediated delivery of CA5-HIF into wounds can significantly improve angiogenesis and overall wound healing in a model of diabetic ulceration. Having secured the license to CA5 for use in wound healing applications from JHU, Canton is now positioning the product for advancement into clinical development. Towards this end, the company has evaluated EP based delivery systems suitable for use in the clinical setting. These efforts have culminated in a partnership with Ichor Medical Systems, Inc. to access the company's EP technology for delivery of the CA5 DNA. By providing a "clinic ready" EP technology with a substantial database of pre-clinical and clinical usage, this agreement will greatly facilitate the development of the CA5 product. Building on the promising pre-clinical data generated to date, the objective of the proposed STTR program is to bring the CA5 product candidate into clinical testing. The program for the STTR project is based on informal guidance from FDA CBER that was obtained by Canton. The FDA letter specifies the scope and nature of the initial pre- clinical proof of concept including demonstration of efficacy, biodistribution and toxicity in the diabetic mouse model. Specifically, STTR Phase 1 will comprise additional pre- clinical testing conducted by Canton researchers to further characterize the safety and efficacy of CA5 delivery in the murine model of wound healing using the Ichor "clinic ready" EP device. PUBLIC HEALTH RELEVANCE: Therapy to Improve Wound Healing with DNA Expression Vector for HIF 11 and Electroporation Impaired wound healing is a tremendous problem for individuals with diabetes. Patients with diabetes are at risk for developing foot ulcers. These non-healing ulcerations on the foot are disabling, and their progression leads to amputation of the lower extremity. Diabetes is the most frequent cause for lower extremity amputation in the United States. Based on a decade of research at Johns Hopkins University, Canton Biotechnologies Inc has been created to develop a technology with potential for improving wound healing in diabetic individuals. The approach is based on electroporation (EP) mediated delivery of a DNA expression vector encoding CA5-HIF to the wound. These efforts have culminated in a partnership with Ichor Medical Systems, Inc. to access the company's "clinic ready" EP device for delivery of the CA5 DNA. Building on the promising pre- clinical data generated to date, the objective of the proposed STTR program is to bring the CA5 product candidate into clinical testing.

描述（由申请人提供）：使用 HIF 11 的 DNA 表达载体和电穿孔改善伤口愈合的疗法对于糖尿病患者来说，伤口愈合受损是一个巨大的问题。糖尿病患者有发生足部溃疡的风险。足部这些无法愈合的溃疡会导致患者致残，其进展会导致下肢截肢。在美国，糖尿病是导致下肢截肢的最常见原因。基于约翰·霍普金斯大学十年的研究，Canton Biotechnologies Inc 的成立旨在开发一种有潜力改善糖尿病患者伤口愈合的技术。该技术基于表达耐氧、高活性的转录因子缺氧诱导因子 11 (CA5-HIF)。该方法基于电穿孔 (EP) 介导的将编码 CA5-HIF 的 DNA 表达载体递送至伤口。使用研究级 EP 设备，我们证明了 CA5 转染后 HIF 持续表达，导致重要血管生成肽（包括 VEGF、PLGF、PDGF-B、血管生成素 1 和血管生成素 2）的 mRNA 表达上调。具有切除伤口的糖尿病小鼠已证明，EP 介导的 CA5-HIF 递送到伤口中可以显着改善糖尿病模型中的血管生成和整体伤口愈合溃疡。 Canton 已获得约翰霍普金斯大学 (JHU) 的 CA5 用于伤口愈合应用的许可，目前正将该产品定位为推进临床开发。为此，该公司评估了适合在临床环境中使用的基于 EP 的输送系统。这些努力最终与 Ichor Medical Systems, Inc. 合作，利用该公司的 EP 技术来输送 CA5 DNA。通过提供“临床就绪”的 EP 技术以及临床前和临床使用的大量数据库，该协议将极大地促进 CA5 产品的开发。基于迄今为止产生的有希望的临床前数据，拟议的 STTR 计划的目标是将 CA5 候选产品纳入临床测试。 STTR 项目的计划基于 Canton 获得的 FDA CBER 的非正式指导。 FDA 的信函详细说明了初始临床前概念验证的范围和性质，包括在糖尿病小鼠模型中证明功效、生物分布和毒性。具体来说，STTR 第一阶段将包括由 Canton 研究人员进行的额外临床前测试，以进一步表征使用 Ichor“临床就绪”EP 设备在小鼠伤口愈合模型中递送 CA5 的安全性和有效性。公共健康相关性：使用 HIF 11 的 DNA 表达载体和电穿孔改善伤口愈合的治疗对于糖尿病患者来说，伤口愈合受损是一个巨大的问题。糖尿病患者有发生足部溃疡的风险。足部这些无法愈合的溃疡会导致患者致残，其进展会导致下肢截肢。在美国，糖尿病是导致下肢截肢的最常见原因。基于约翰·霍普金斯大学十年的研究，Canton Biotechnologies Inc 的成立旨在开发一种有潜力改善糖尿病患者伤口愈合的技术。该方法基于电穿孔 (EP) 介导的将编码 CA5-HIF 的 DNA 表达载体递送至伤口。这些努力最终与 Ichor Medical Systems, Inc. 合作，使用该公司的“临床就绪”EP 设备来输送 CA5 DNA。基于迄今为止产生的有希望的临床前数据，拟议的 STTR 计划的目标是将 CA5 候选产品纳入临床测试。