Gene therapy: an attractive concept and maybe more. Gene therapy (Table 2) in articular joint tissues can be used as a drug delivery system to modify or reestablish the balance between catabolic/anabolic factors or to modulate proinflammatory cytokines. Ideally, this must be done to the cell or must be tissue specific. The potential for the use of biologic molecules as therapeutic agents is limited. Lately, much attention has been focused on the use of gene transfer techniques. Their potential for the treatment of OA is of very significant interest, since a consistently high local concentration of the therapeutic protein in the joint can be provided and sustained delivery maintained over time. Several strategies to replace defective or deficient protein products are now under study (Table 2). Treatment approaches consist of various ex vivo or in vivo techniques using viral or nonviral vectors (102). One strategy consists of insertion into the cells of a gene enabling the production of a protein not normally expressed or expressed in low and insufficient amounts by the OA cells. The viral system is favored because it generally allows for a very effective transfer to a large percentage of cells while maintaining a sustained high level of protein expression that can be extended over significant periods of time. Ex vivo transfer of marker genes to OA cells has been demonstrated in experimental models with the use of a retroviral vector (89).

Table 2. Gene therapy for osteoarthritis*

*

In both cartilage and synovium, catabolic factors (for example, metalloproteases [MMPs], nitric oxide [NO]) and cytokines (for example, interleukin-1β [IL-1β], tumor necrosis factor α [TNFα]) should be either reduced or eliminated. In contrast, some growth factors and the cytokine receptor antagonist (interleukin-1Ra [IL-1Ra]) or soluble receptors (soluble IL-1 receptor type II [sIL-1RII], soluble tumor necrosis factor receptor [sTNFR]) should be stimulated.

Potential targets

 Cartilage

  Catabolic factors (for example, MMPs, NO)

  Anabolic factors (growth factors)

  Apoptotic factors (for example, caspases, ceramides)

 Synovium

  Cytokines (for example, IL-1β, TNFα)

  Antiinflammatory cytokines (IL-4, IL-10, IL-13)

  Cytokine receptor antagonist (IL-1Ra)

  Soluble receptors (sIL-1RII, sTNFR)

Strategies

 Gene replacement

 Gene addition

 Gene control

The selection or combination of the gene(s) that would offer the best protection against OA remains to be determined. The transfer of genes such as IL-1Ra, IL-10, and IL-13 has been studied using OA or inflammatory animal models (103). However, more specifically with regard to OA, the use of IL-1Ra gene therapy has elicited much attention. The rationale is based mainly on the fact that this antagonist has the ability in vitro to arrest cartilage degradation and in vivo to reduce the progression of experimental OA (30, 89, 90)