Gene therapy for cartilage healing

Articular cartilage has only a limited capacity for repair. Only in the event of damage that extends through to the underlying vasculature and marrow of the subchondral bone will a repair response be initiated; populations of mesenchymal stem cells infiltrate the lesion and synthesize space-filling tissue. This repair tissue is of inferior composition and degenerates with time. Gene transfer strategies, however, may provide methods to stimulate these cells toward the synthesis of more suitable repair tissue that is functionally closer to normal articular cartilage. Through the in vitro transfer of genes encoding certain growth factors such as transforming growth factor-β (TGF-β), insulin-like growth factor 1 (IGF-1) and bone morphogenetic protein 2 (BMP-2) we have found it possible to stimulate chondrogenesis of bone marrow stem cells as well as increase the synthesis and deposition of extracellular matrix components by chondrocytes. In contrast to the exploration of complex ex vivo methods for engineering cartilaginous tissues, we have been undertaking practical methods for transferring genes encoding chondrogenic growth factors directly to cells infiltrating osteochon-dral defects in a rabbit model. For this approach, vectors suitable for gene delivery in vivo are absorbed into a biologically compatible matrix and implanted directly into freshly generated osteochondral lesions. Using either recombinant adenoviral vectors or plasmid DNAs we have shown that cells entering the defect can infiltrate the implanted matrix, interact with the vector and express the transgene product for up to 3 weeks. This method is currently being evaluated for its effectiveness in repairing osteochondral defects following the delivery of chondrogenic genes such as TGF-β, BMP-2 and IGF-1.