title: Clinical responses to gene therapy in joints of two subjects with rheumatoid arthritis.
abstract: 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-1beta. 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.
authors.affiliation: Department of Orthopedic Surgery, University of Düsseldorf School of Medicine, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Wehling
authors.forename: Julio
authors.initials: J
authors.lastname: Reinecke
authors.forename: Axel W A
authors.initials: AW
authors.lastname: Baltzer
authors.forename: Markus
authors.initials: M
authors.lastname: Granrath
authors.forename: Klaus P
authors.initials: KP
authors.lastname: Schulitz
authors.forename: Carl
authors.initials: C
authors.lastname: Schultz
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Krauspe
authors.forename: Theresa W
authors.initials: TW
authors.lastname: Whiteside
authors.forename: Elaine
authors.initials: E
authors.lastname: Elder
authors.forename: Steven C
authors.initials: SC
authors.lastname: Ghivizzani
authors.forename: Paul D
authors.initials: PD
authors.lastname: Robbins
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Evans
mesh_terms: D000328:Adult; D001172:Arthritis, Rheumatoid / Q000628:therapy*; D015152:Blotting, Northern; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008662:Metacarpophalangeal Joint / Q000473:pathology*; D008875:Middle Aged; D059408:Pain Management; D012190:Retroviridae / Q000235:genetics; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D020782:Matrix Metalloproteinases