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

肌营养不良症肢体静脉生理盐水灌注的安全性和可行性研究 由于其遗传基础和目前缺乏治愈性治疗，肌营养不良症是极好的 基因治疗的候选疾病。开发此类疗法的一个重要步骤是提供 在全身给药前，将遗传物质转移到单肢，以证明安全性和有效性。的 在实验动物中研究的各种单肢递送方法，高压，高容量 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， 适用因在本计画中，我们将进行经静脉单肢灌注的安全性与可行性研究 用生理盐水治疗肌肉萎缩症。本研究设计为剂量递增 安全性研究，灌注参数以逐步方式增加，并对两者进行仔细监测 bcal和全身毒性。这一设计还将使我们能够解决多个后勤方面的固有问题 从动物到人类的肌肉萎缩症，包括镇痛，血管通路和更大的 输注体积。在具体目标1中，我们将研究患有肢带型或贝克型肌营养不良症的年轻人 从0.05 mL盐水/ml肢体体积的输注开始，逐渐增加至最大0.40 mL/mL。一个 独立的安全监测员将审查每名受试者的数据（灌注参数、实验室和临床 测试）并且必须批准下一个受试者的计划灌注参数。通过这项研究，我们将 确定安全的最大灌注参数，并记录液体输送到 T2 MRI检查。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肌营养不良症开始于0.05 ml盐水/ml肢体体积，并逐步升级至 根据具体目标1确定的最大体积不大于最小风险。本研究将 提供关于灌注技术本身的必要安全性和可行性数据，为 未来的区域肢体传递研究的积极基因治疗。结果将普遍适用于 许多不同试剂（寡核苷酸、质粒-DNA和病毒递送系统）的单肢递送， 给不同年龄、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.