Transfer of IL-1Ra cDNA to Osteoarthritic Knee

描述（由申请人提供）：IL-1 Ra cDNA转移至关节滑膜衬里在类风湿性关节炎和骨关节炎动物模型中显示出安全性和有效性。一项I期研究拟评估局部，体内基因转移关节骨关节炎，这种类型的基因治疗的一个很好的候选人的适用性。在该方案中，将通过体内基因转移将IL-1 Ra cDNA递送至9名患有膝关节骨关节炎的受试者的膝关节。重组血清型2腺相关病毒（AAV.IL-1 Ra）将用于此目的，转基因表达由人巨细胞病毒立即早期启动子驱动。临床级AAV.IL-1 Ra将由国家基因载体实验室生产。以剂量递增的方式，3名受试者将在全膝关节置换术前12周在一个膝关节中各自接受5x 1011（低剂量）、5x 1012（中剂量）或5x 1013（高剂量）病毒颗粒。在注射病毒前即刻和关节置换手术前即刻，从膝关节抽吸滑液，并抽取外周血。将通过测量滑液的IL-1 Ra浓度来评估关节内转基因表达。还将测量外周血中的IL-1 Ra浓度。将检查关节置换手术时回收的关节组织中是否存在整合型和游离型病毒基因组以及转基因表达。将在病毒递送前即刻和关节置换术前即刻通过关节MR成像评价可能的关节内不良事件。通过分析注射病毒前即刻、关节置换术前即刻以及关节置换术后3、6和12个月采集的外周血样本，收集其他安全性信息。如果该方案能够以安全有效的方式产生相关水平的关节内IL-1 Ra转基因表达，它将为随后的干预性研究奠定基础，以确定骨关节炎的疗效。

DESCRIPTION (provided by applicant): Transfer of IL-1Ra cDNA to the synovial linings of joints has shown both safety and efficacy in animal models of rheumatoid- and osteo-arthritis. A phase I study is proposed to assess applicability of local, in vivo gene transfer to joints with osteoarthritis, an excellent candidate for this type of gene therapy. In this protocol IL-1Ra cDNA will be delivered by in vivo gene transfer to the knee joints of 9 subjects with osteoarthritis of the knee. A recombinant, serotype 2, adeno-associated virus (AAV.IL-1Ra) will be used for this purpose, with transgene expression driven by the human cytomegalovirus immediate-early promoter. Clinical grade AAV.IL-1Ra will be produced by the National Gene Vector Laboratory. In a dose-escalation manner, 3 subjects will each receive 5x1011 (low dose), 5x1012 (middle dose) or 5x1013 (high dose) viral particles in one knee joint, twelve weeks before total knee joint replacement surgery. Synovial fluid will be aspirated from the knee joints, and peripheral blood withdrawn, immediately before injection of the virus, and again immediately before joint replacement surgery. Intraarticular transgene expression will be assessed by measuring the IL- 1Ra concentration of the synovial fluid. IL-1Ra concentrations in peripheral blood will also be measured. Articular tissues recovered at the time of joint replacement surgery will be examined for the presence of integrated and episomal viral genomes, and for transgene expression. Possible adverse intraarticular events will be evaluated by MR imaging of joints immediately before viral delivery and immediately before joint replacement surgery. Additional safety information will be gathered by analysis of peripheral blood samples drawn immediately before injection of virus, immediately before joint replacement surgery, and 3, 6 and 12 months after joint replacement surgery. If this protocol is able to generate relevant levels of intraarticular IL-1Ra transgene expression in a safe and efficient manner, it will set the stage for a subsequent interventional study to determine efficacy in osteoarthritis.