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

生理盐水经肢体静脉灌注的安全性和可行性研究

• 批准号: 7938901
• 负责人: WILLIAM J POWERS
• 金额: $ 22.37万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7938901
• 关键词: Absence of pain sensation; Address; Adult; Age; Animals; Becker Muscular Dystrophy; Blood Vessels; Candidate Disease Gene; Cardiovascular Physiology; Child; Data; Development; Dose; Duchenne muscular dystrophy; Feasibility Studies; Future; Genetic; Genetic Materials; Human; Infusion procedures; Isolated limb perfusion; Laboratories; Limb structure; Limb-Girdle Muscular Dystrophies; Liquid substance; Magnetic Resonance Imaging; Methods; Monitor; Muscle; Muscular Dystrophies; Nerve; Normal saline; Oligonucleotides; Patients; Perfusion; Renal function; Research; Safety; Saline; System; Techniques; Testing; Toxic effect; Venous; Viral; base; design; gene therapy; human subject; minimal risk; plasmid DNA; pressure; research clinical testing; safety study; young adult

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.

人类肌肉营养不良中透性肢体灌注的安全性和可行性研究 由于其遗传基础和当前缺乏治疗疗法，肌肉营养不良是极好的 基因疗法的候选疾病。这种疗法发展的重要步骤是交付 遗传物质到一个肢体，以在系统给药之前证明安全性和功效。的 在实验动物，高压，高体积中研究的各种单肢递送方法 肢体肢体灌注显示出有效，临床实用且通常的最大潜力 适用的。在这个项目中，我们将对透性单肢灌注进行安全性和可行性研究 患有肌肉营养不良的人类受试者的盐水正常。该研究被设计为剂量升级 灌注参数的安全研究以逐步的方式增加，并仔细监测两者 BCAL和全身毒性。该设计还将使我们能够解决固有的多个后勤方面 从动物到人类患有肌肉营养不良的人，包括镇痛，血管通道和较大的 输注体积。在特定目标1中，我们将研究患有肢体束或贝克肌营养不良的年轻人 从输注0.05 ml盐水 /毫升的肢体体积开始，最大升级为.40 mL /ml。一个 独立安全监控器将审查每个受试者的数据（灌注参数，实验室和临床 测试），必须批准下一个主题的计划灌注参数。从这项研究中，我们将 确定安全的最大灌注参数，并记录流体输送程度 T2 MRI的肌肉。在特定目标2中，我们将在患有儿童的儿童中进行类似的剂量升级研究 Duchenne肌肉营养不良症从.05 mL盐水 /毫升肢体体积开始，并升级为 由特定目标1确定的最大体积不超过最小风险。这项研究会 提供有关灌注技术本身的必要安全性和可行性数据，以提供基础 活跃基因治疗的未来区域肢体输送研究。结果通常适用于 许多不同不同药物（寡核苷酸，质粒-DNA和病毒输送系统）的单肢递送和 对于不同年龄的患者，患有不同类型的肌肉营养不良。