Novel Integrated Clinical Electroporation Technology for Dermal DNA Vaccination

描述（由申请人提供）：DNA疫苗接种有希望用于广泛的治疗和预防适应症，但尚未证明在人类中的临床成功。该领域的共识是，常规递送方法的次优效力和低效率是一个关键障碍。体内电穿孔（EP）的使用提供了多种组织中DNA摄取和表达的多对数增加。当用于DNA免疫时，EP介导的肌内（i.m.）或皮内（i.d.）与常规注射相比，DNA疫苗的递送显著增强了免疫应答的强度和一致性。该技术临床实施的主要挑战是提供能够以适合临床使用的方式安全、有效和可重现输送的器械。由于其可及性和皮肤中抗原呈递细胞谱的存在，i.d. DNA免疫是特别令人感兴趣的。与其他DNA递送至皮肤的方法相比，EP因其递送效率、高水平抗原表达、强大的剂量能力和跨细胞类型的实用性而处于有利地位。Ichor开发了EP平台技术（TriGrid输送系统-TDS），旨在临床环境中安全，有效和可重现的DNA输送。基于其在开发用于i.m.输送的电生理器械（TDS-IM）方面的经验，该器械目前正处于多种适应症的临床研究中，该公司处于有利地位，可以开发i.d.交付.为此，Ichor开始开发用于EP介导的i.d. DNA免疫（TDS-ID），目的是提供一种简单、可重复的递送装置，以支持商业疫苗开发。初步结果表明，在多个物种中诱导有效的免疫应答。现在的努力集中在开发适用于临床试验的设备上。尚未解决的中心设计问题是选择能够实现一致i. d.的注射技术。与EP器械集成时的DNA分布。在I期，多个候选i.d.注射技术将在人皮肤（猪）的动物模型中表征。评价标准包括：1）i.d.的大小和一致性。通过报告基因表达评估的递送和2）针对模型抗原引发的免疫应答的定量和定性分析。拟议的研究将为最终确定器械设计提供基础，并为促进合作/协作提供有价值的数据集。如果实现了第一阶段的可行性里程碑，第二阶段将包括开发和测试适用于人体临床试验的集成TDS-ID设备。第二阶段的总体目标是向美国FDA提交器械主文件，为启动Ichor或其合作伙伴开发的候选DNA疫苗的TDS-ID给药的临床试验提供基础。公共卫生相关性：该项目将评估一种新的电穿孔介导的皮内（i.d.）DNA疫苗递送。通过提供一种简单的方法来实现有效和一致的i.d. DNA疫苗输送，拟议的设备可以促进DNA疫苗的适应症，包括癌症，传染病和过敏。

DESCRIPTION (provided by applicant): DNA vaccination is promising for a wide range of therapeutic and preventive indications but is yet to demonstrate clinical success in humans. Consensus in the field is that suboptimal potency and inefficiency of conventional delivery methods is a key hurdle. The use of in vivo electroporation (EP) provides multi-log increases in DNA uptake and expression in a variety of tissues. When used for DNA immunization, EP-mediated intramuscular (i.m.) or intradermal (i.d.) delivery of DNA vaccines significantly enhances the magnitude and consistency of immune response compared to conventional injection. The central challenge for the clinical implementation of this technology is the provision of devices capable of safe, effective, and reproducible delivery in a manner appropriate for clinical use. Due to its accessibility and the presence of a spectrum of antigen presenting cells in the skin, i.d. DNA immunization is of particular interest. When compared to other methods of DNA delivery to skin, EP is well positioned due to its delivery efficiency, high level antigen expression, robust dose capacity, and utility across cell types. Ichor has developed platform EP technology (TriGrid Delivery System-TDS) designed for safe, effective, and reproducible DNA delivery in the clinical setting. Based on its experience in the development of an EP device for i.m delivery (TDS-IM) that is currently in clinical studies for multiple indications, the company is well positioned to develop technology for i.d. delivery. Towards this end, Ichor initiated development of prototype devices for EP mediated i.d. DNA immunization (TDS-ID) with the objective of providing a simple, reproducible delivery device to support commercial vaccine development. Preliminary results demonstrate induction of potent immune responses in multiple species. Efforts are now focused on development of devices suitable for use in clinical trials. A central design issue yet to be addressed is the selection of an injection technology capable of achieving consistent i.d. DNA distribution when integrated with the EP device. In Phase I, performance of multiple candidate i.d. injection technologies will be characterized in an animal model of human skin (swine). The criteria for evaluation will include: 1) magnitude and consistency of i.d. delivery as assessed by reporter gene expression and 2) quantitative and qualitative analysis of the immune responses elicited against a model antigen. The proposed studies will provide the basis for finalizing device design as well as a valuable data set to facilitate partnering/collaboration. If the feasibility milestones for Phase I are achieved, Phase II will comprise development and testing of an integrated TDS-ID device suitable for use in human clinical trials. The overall objective of Phase II would be the submission of a device master file to the US FDA to provide the foundation to initiate clinical testing of TDS-ID administration of DNA vaccine candidates developed by Ichor or its partners. PUBLIC HEALTH RELEVANCE: The proposed project will evaluate the basic feasibility of a novel integrated device for electroporation mediated intradermal (i.d.) DNA vaccine delivery. By providing a simple method to achieve effective and consistent i.d. DNA vaccine delivery, the proposed device could facilitate DNA vaccines for indications including cancer, infectious disease and allergy.