Development of an Autologous Macrophage-based Adoptive Gene Transfer Strategy to Treat Posttraumatic Osteoarthritis (PTOA) and Osteoarithritis (OA).

摘要

OA is the most common degenerative joint disease, and ~12% of all OA are resulted from an acute trauma to the joint and are referred to as PTOA. There is no cure for PTOA or OA. This Discovery Award project seeks to obtain proof-of-concept type of evidence for the feasibility of and efficacy for an innovative autologous macrophage-based anti-catabolic and pro-chondrogenic combination adoptive gene therapy for treatment of PTOA. The rationale for the use of macrophages as the cell vehicle for targeted delivery and confined expression of the transgene(s) is based on definitive evidence that a) PTOA development is associated with both acute and chronic inflammation of the synovium; and b) synovial inflammation triggers massive infiltration of activated macrophages. The idea of the combination macrophage-based adoptive gene therapy with both an anti-catabolic gene (IL-1ra or IL-1Beta shRNA) and a pro-chondrogenic gene (TGFBeta3) is based on the assumption that comprehensive treatment of a disease with complex pathophysiology, such as PTOA, will require concerted treatments at multiple phases of the diseases. The proposed study will test two hypotheses: 1) the autologous macrophage-based adoptive gene transfer strategy can effectively deliver and confine expression of an anti-catabolic gene (IL-1ra or IL-1Beta shRNA) along with a chondrogenic gene (TGFBeta3) in the inflamed areas within the synovium of the PTOA joint; and 2) the IL-1ra (or IL-1Beta shRNA) and TGFBeta3 combination autologous macrophage-based adoptive gene transfer strategy will reduce PTOA symptoms and promote articular cartilage regeneration in a mouse PTOA model.