Improve Wound Healing with HIF-CA5 DNA Vector and Electroporation

描述（由申请人提供）：利用HIF - 11和电穿孔DNA表达载体促进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。糖尿病患者有患足部溃疡的风险。这些无法愈合的足部溃疡是致残的，它们的发展导致下肢截肢。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，广州生物技术有限公司已经成立，以开发一种有可能改善糖尿病患者伤口愈合的技术。这项技术是基于表达一种抗氧、高活性形式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表达载体递送到伤口。使用研究级EP设备，我们证明了CA5转染后HIF的持续表达，导致重要血管生成肽的mRNA表达上调，包括VEGF、PLGF、PDGF-B、血管生成素1和血管生成素2。临床前实验表明，EP介导的CA5-HIF进入创面可以显著改善糖尿病溃疡模型的血管生成和整体创面愈合。在从JHU获得CA5用于伤口愈合应用的许可后，广州现在正将该产品推向临床开发。为此，该公司已经评估了适合临床使用的基于EP的输送系统。这些努力最终与Ichor医疗系统公司合作，获得该公司的EP技术，用于递送CA5 DNA。通过提供具有大量临床前和临床使用数据库的“临床就绪”EP技术，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项目的目标是将CA5候选产品带入临床测试。STTR项目的计划是基于广州获得的FDA CBER的非正式指导。FDA的信函详细说明了初始临床前概念证明的范围和性质，包括在糖尿病小鼠模型中的有效性、生物分布和毒性证明。具体来说，STTR第一阶段将包括由广州研究人员进行的额外临床前测试，以进一步表征CA5在使用Ichor“临床就绪”EP设备的小鼠伤口愈合模型中的安全性和有效性。

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.