Computer-Assisted Hydrodynamic Gene Delivery for Hemophilia Gene Therapy

描述（由申请人提供）：开发新的和改进的方法，用于安全、位点特异性和有效的基因递送，已成为基因治疗研究的主要焦点。为了加速这一过程，我们开发了一种计算机控制的注射装置，用于流体动力学基因递送到体内不同器官，特别是肝脏。采用图像引导的导管插入技术，我们已经证明了在猪的计算机辅助流体动力学基因传递到猪肝是有效和安全的。在本提案中概述的研究中，我们将使用血友病B犬作为动物模型，评价我们新开发的基因递送系统治疗血友病B的有效性和安全性。该研究的总体目标是建立一种微创、可靠和安全的人类基因治疗方法。 在具体目标1中，我们将采用图像引导的肝脏特异性流体动力学基因递送的程序来优化用于基因递送到狗肝脏的流体动力学参数。在具体目标2中，我们将表征流体动力学基因递送对转基因表达的持续性、对组织毒性的影响、针对转基因产物的潜在免疫应答以及转基因的组织分布的长期影响。具体目标3被设计为评估向相同动物重复流体动力学基因递送的有效性。在具体目标4中，我们将对治疗血友病B犬血友病的优化程序进行临床前评价，并表征治疗的长期效应。 这项转化研究旨在验证新开发的计算机控制的基因递送装置，并建立临床适用的程序。从研究中收集的数据对于临床试验的准备至关重要。如果成功完成，拟议的研究将提供一种新的基因递送技术，并将显着推进基因治疗领域。 公共卫生相关性：血友病B是一种X连锁遗传性出血性疾病，约25,000例男性中有1例发生。它是第二种最常见的血友病类型。本研究旨在开发一种计算机控制的基因传递系统，用于血友病B的基因治疗。

DESCRIPTION (provided by applicant): Development of new and improved methods for a safe, site specific and efficient gene delivery has become a major focus in gene therapy research. To accelerate the process, we have developed a computer-controlled injection device for hydrodynamic gene delivery to different organs in vivo, particularly to liver. Employing an image-guided catheter insertion technique, we have demonstrated in pigs that the computer-assisted hydrodynamic gene delivery to pig liver is effective and safe. In the study outlined in this proposal, we will evaluate the effectiveness and safety of our newly developed gene delivery system for treatment of hemophilia B using hemophilia B dogs as an animal model. The overall objective of the proposed study is to establish a minimally invasive, reliable and safe procedure for human gene therapy. In specific aim 1, we will employ the procedure of image-guided, liver specific hydrodynamic gene delivery to optimize the hydrodynamic parameters for gene delivery to dog liver. In specific aim 2, we will characterize the long-term impact of the hydrodynamic gene delivery with respect to persistence of transgene expression, effect on tissue toxicity, potential immune response against transgene product, and tissue distribution of the transgene. Specific aim 3 was designed to assess the effectiveness of repeated hydrodynamic gene delivery to the same animals. In specific aim 4, we will perform pre-clinical evaluation of the optimized procedure for treatment of hemophilia in hemophilia B dogs and characterize the long-term effects of the treatment. This translational research is designed to validate a newly developed computer-controlled device for gene delivery and to establish a clinically applicable procedure. Data collected from the study will be critical for preparation of clinical trials. If successfully accomplished, the proposed study will provide a new technology for gene delivery and will significantly advance the field of gene therapy. PUBLIC HEALTH RELEVANCE: Hemophilia B is an x-linked inherited bleeding disorder occurring in about one in ~25,000 male birth. It is the second most common type of hemophilia. The study aims at developing a computer-controlled gene delivery system for treatment of hemophilia B using gene therapy approach.