Novel Integrated Clinical Electroporation Technology for Dermal DNA Vaccination

描述(申请人提供)：DNA疫苗有望用于广泛的治疗和预防适应症，但尚未在人类身上证明临床成功。该领域的共识是，传统给药方法的效力不佳和效率低下是一个关键障碍。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介导的肌肉注射(I.M.)或皮内(I.D.)与常规注射相比，DNA疫苗的交付显著增强了免疫反应的大小和一致性。这项技术临床应用的主要挑战是提供能够以适合临床使用的方式安全、有效和可重复地提供的设备。由于它的可及性和皮肤中存在一系列抗原提呈细胞，I.D.DNA免疫尤其令人感兴趣。与其他向皮肤输送DNA的方法相比，EP由于其输送效率、高水平的抗原表达、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开发了平台EP技术(TriGrid Delivery System-TDS)，旨在安全、有效和可重复地在临床环境中传递DNA。基于其开发用于肌注的EP设备(TDS-IM)的经验，该设备目前正处于多适应症的临床研究中，该公司处于有利地位，可以开发用于I.M.的技术。送货。为此，Ichor开始了EP介导的身份识别原型装置的开发。DNA免疫(TDS-ID)，目的是提供一种简单、可重复的递送装置，以支持商业疫苗的开发。初步结果表明，在多个物种中都能诱导有效的免疫反应。目前的工作重点是开发适用于临床试验的设备。一个尚未解决的核心设计问题是选择一种能够实现一致身份识别的注射技术。当与EP设备集成时，DNA分布。在第一阶段，多名候选人身份证明的表现。注射技术将以人类皮肤(猪)的动物模型为特征。评价标准将包括：1)身份证明的大小和一致性。通过报告基因表达来评估递送，以及2)针对模型抗原引起的免疫反应的定量和定性分析。拟议的研究将为最终确定设备设计提供基础，并提供宝贵的数据集，以促进伙伴关系/协作。如果第一阶段的可行性里程碑得以实现，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将是向美国FDA提交一份设备主文件，为启动Ichor或其合作伙伴开发的候选DNA疫苗的TDS-ID给药的临床测试奠定基础。公共卫生相关性：拟议的项目将评估一种新型集成电穿孔皮内注射(I.D.)装置的基本可行性。DNA疫苗的投放。通过提供一种简单的方法来实现有效和一致的身份识别。在DNA疫苗的交付方面，拟议的设备可以促进DNA疫苗用于癌症、传染病和过敏等适应症。

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.