Clinical Responses to Gene Therapy in Joints of Two Subjects with Rheumatoid Arthritis
Clinical Responses to Gene Therapy in Joints of Two Subjects with Rheumatoid Arthritis
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DOI：
10.1089/hum.2008.075
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发表时间：
2009-02-01
影响因子：
4.2
通讯作者：
Evans, Christopher H.
中科院分区：
文献类型：
--
作者：
Wehling, Peter;Reinecke, Julio;Evans, Christopher H.
本文提供了人类关节炎基因治疗的临床反应的第一个证据。两名患有类风湿性关节炎的受试者接受了人白细胞介素 1 受体拮抗剂 (IL-1Ra) cDNA 的离体关节内递送。为了实现这一目标，用携带 IL-1Ra 作为转基因的逆转录病毒 MFG-IRAP 转导自体滑膜成纤维细胞，或保留作为未转导的对照。有症状的掌指（MCP）关节被注射对照或转导细胞。根据疼痛情况对关节进行临床评估；还测量了 MCP 接头 1 的周长。 4周后，关节接受滑膜切除术。两名受试者均未出现不良事件。第一个受试者对基因转移反应显着，疼痛和肿胀明显迅速减轻，这种情况持续了整个 4 周的研究。值得注意的是，接受 IL-1Ra cDNA 的关节受到保护，免受研究期间发生的耀斑影响。滑膜切除后回收的 RNA 分析显示 IL-1Ra 表达增强，基质金属蛋白酶 3 和 IL-1 beta 表达减少。第二名受试者的疼痛和肿胀也减轻了。因此，至少在短期内，可以安全地完成向人类类风湿关节的基因转移，从而产生临床益处。使用这种离体程序，转基因在关节内持续至少 1 个月。需要进一步的临床研究。
This paper provides the first evidence of a clinical response to gene therapy in human arthritis. Two subjects with rheumatoid arthritis received ex vivo, intraarticular delivery of human interleukin-1 receptor antagonist (IL-1Ra) cDNA. To achieve this, autologous synovial fibroblasts were transduced with a retrovirus, MFG-IRAP, carrying IL-1Ra as the transgene, or remained as untransduced controls. Symptomatic metacarpophalangeal (MCP) joints were injected with control or transduced cells. Joints were clinically evaluated on the basis of pain; the circumference of MCP joint 1 was also measured. After 4 weeks, joints underwent surgical synovectomy. There were no adverse events in either subject. The first subject responded dramatically to gene transfer, with a marked and rapid reduction in pain and swelling that lasted for the entire 4 weeks of the study. Remarkably, joints receiving IL-1Ra cDNA were protected from flares that occurred during the study period. Analysis of RNA recovered after synovectomy revealed enhanced expression of IL-1Ra and reduced expression of matrix metalloproteinase-3 and IL-1 beta. The second subject also responded with reduced pain and swelling. Thus, gene transfer to human, rheumatoid joints can be accomplished safely to produce clinical benefit, at least in the short term. Using this ex vivo procedure, the transgene persisted within the joint for at least 1 month. Further clinical studies are warranted.