Gene Therapy For Arthritis

Author: Charlie Lundquist

Arthritis affects nearly a third of the nations population, yet none of the current drugs or treatments for arthritis alters the course of the disease, and joint replacements are nowhere near as good as the original healthy joint. In the future, gene therapy may provide the answer, and a cure for arthritis. Gene therapy is currently being evaluated for its abilities in inducing stem cell differentiation into healthy cartilage and its ability to transfer genes that could aid in treating the symptoms of arthritis

Stem Cell Differentiation

The problem with current methods of creating cartilage grafts is that mature chondrocytes, such as those obtained in a biopsy, have a limited capacity to reproduce. They reproduce slowly and only divide a certain number of times. Adult stem cells have an unlimited capacity to reproduce and can differentiate into any kind of cell under the right conditions. Ideally, a cartilage graft would use stem cells differentiated into mature chondrocytes[i]. More cells would be produced and all the cells would be of the correct type. The only problem is getting the stem cells to differentiate into what you want.

Genetic modulation could serve this purpose by directing the differentiation into chondrocytes. Currently studies around the world are looking at differentiating stem cells by using recombinant DNA vectors. Basically, a bacteria or virus is encoded with a gene that expresses a protein that signals the stem cell to differentiate into a chondrocyte. The bacteria then infect the stem cell and incorporate its DNA. The stem cell uses the bacterial DNA to make the desired protein. Signals within the cell detect the protein and tell the cell to differentiate into a chondrocyte. Many potential proteins have been identified, but the most important are Sox8 and Sox9 because they are most directly associated with differentiation.

Gene Transfer For Treatment of Arthritis

Two projects began in 2006 that could provide a treatment for non-specific arthritis through gene therapy. One project, led by Dr. Christopher Evans at Harvard University, is trying to create a cell factory that delivers medicine to an affected joint. The premise is to use a bacterial or viral vector to insert a specific gene into the cells surrounding a joint. The cells would then begin to produce interleukin-1 inhibitor protein, which negates a substance that causes swelling and immune response in joints. Trials in horses and rabbits have shown significant improvement in symptoms long-term (up to one year). Clinical trials in humans began in early 2007 and are ongoing[ii].

The second project is being conducted by a company in Maryland called TissueGene. This company has created a genetically modified cell culture that produces a protein which promotes growth in damaged cartilage. The protein could induce enough growth and remodeling in the joint to eliminate symptoms entirely. Clinical trials in humans also began early in 2007 on patients undergoing total joint replacement surgery. The cells were injected several weeks before the joint was taken out and the joints were evaluated for cartilage regeneration. Transfection of TGF-β cDNA expression vectors into fibroblasts (NIH 3T3-TGF-β1) generated the genetically modified culture which produced hyaline and fibrous cartilage when injected into a damaged joint. The results of clinical trials are still under evaluation.

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[i] Heng, B. C., T. Cao, and E. H. Lee. "Directing Stem Cell Differentiation into the Chondrogenic Lineage in Vitro." Stem Cells 22.7 (2004): 1152-67.

[ii] Dembner, Alice. "Research to Unleash Gene Therapy on Arthritis." Health. Boston Globe August 14 2006.