Safety and Feasibility Study of Transvenous Limb Perfusion with Normal Saline in

生理盐水肢体静脉灌注治疗人类肌营养不良症的安全性和可行性研究 由于它们的遗传基础和目前缺乏治疗方法，肌营养不良症是非常好的。 基因治疗的候选疾病。这种疗法发展的一个重要步骤是提供 在全身给药之前，将遗传物质移植到单个肢体，以证明其安全性和有效性。中的 在实验动物中研究的各种单肢分娩方法，高压，大容量 经静脉肢体灌注显示出最大的潜力，是一种有效的、临床实用的和普遍的 适用。在本项目中，我们将进行经静脉单侧肢体灌注的安全性和可行性研究。 肌肉营养不良的受试者用生理盐水。这项研究被设计为剂量递增 以循序渐进的方式增加灌注参数并对两者进行仔细监测的安全性研究 BCAL和全身毒性。这一设计还将允许我们解决固有的多个后勤方面 从动物到人类的肌营养不良症，包括止痛，血管通路和更大的 输液量。在具体目标1中，我们将研究患有四肢带状或Becker肌营养不良症的年轻人。 从输注0.05毫升生理盐水/毫升肢体体积开始，逐渐增加到最高.40毫升/毫升。一个 独立的安全监测器将审查每个对象(灌注参数、实验室和临床)的数据 测试)，并且必须批准下一受试者的计划灌流参数。从这项研究中，我们将 确定安全的最大灌注参数，并记录液体输送到 T2MRI检查肌肉。在具体目标2中，我们将在儿童中进行类似的剂量递增研究 Duchenne肌营养不良始于0.05毫升生理盐水/毫升肢体体积，并升级到 根据具体目标1确定的不大于最小风险的最大交易量。这项研究将 提供有关灌流技术本身的必要的安全性和可行性数据，为 未来主动基因治疗的区域性肢体输送研究。结果将普遍适用于 多种不同制剂(寡核苷酸、质粒DNA和病毒输送系统)的单肢输送 适用于不同年龄、不同类型的肌营养不良症患者。

Safety and Feasibility Study of Transvenous Limb Perfusion with Normal Saline in Human Muscular Dystrophy Due to their genetic basis and the current lack of curative therapy, the muscular dystrophies are excellent candidate diseases for gene therapies. An essential step in this development of such therapies is delivery of genetic material to a single limb to demonstrate safety and efficacy prior to systemic administration. Of the various methods of single limb delivery studied in experimental animals, high-pressure, high-volume transvenous limb perfusion shows the greatest potential to be an effective, clinically practical and generally applicable. In this project, we will perform a safety and feasibility study of transvenous single limb perfusion with normal saline in human subjects with muscular dystrophy. The study is designed as a dose-escalation safety study with the perfusion parameters increased in a stepwise manner and careful monitoring for both bcal and systemic toxicity. This design will also permit us to address the multiple logistical aspects inherent in going from animals to humans with muscular dystrophy including analgesia, vascular access and larger infusion volumes. In Specific Aim 1, we will study young adults with limb-girdle or Becker muscular dystrophy beginning with infusions of .05 mL saline /ml of limb volume and escalating to a maximum of .40 mL/mL. An independent safety monitor will review data on each subject (perfusion parameters, laboratory and clinical testing) and must approve planned perfusion parameters for the next subject. From this study, we will determine the maximum perfusion parameters that are safe and document the degree of fluid delivery into muscle by T2 MRI. In Specific Aim 2, we will carry out a similar dose escalation study in children with Duchenne muscular dystrophy beginning at .05 ml saline /ml of limb volume and escalating to the maximum volume determined from Specific Aim 1 as posing no greater than minimal risk. This study will provide the necessary safety and feasibility data on the perfusion technique itself to provide the basis for future regional limb delivery studies of active gene therapy. The results will be generally applicable to the single limb delivery of many different agents (oligonucleotides, plasmid-DNA and viral delivery systems) and to patients of different ages with diverse types of muscular dystrophy.