"At the outset, our primary objective was proving the safety of gene therapy, especially for a clinical application to a nonlethal disease, such as arthritis. Once we learned of the adverse events in the X-SCID trial, we decided it was best to extend follow-up of our patients to five years so that there'd be little question about long-term safety," explained Christopher H. Evans, Ph.D., D.Sc., the study's lead author, now director of the Center for Molecular Orthopaedics at Brigham and Women's Hospital and Robert Lovett Professor of Orthopaedic Surgery at Harvard Medical School.
In rheumatoid arthritis, immune system cells called macrophages and lymphocytes colonize the lining of joints where they release proteins called cytokines that modulate communication between the immune cells and synovial cells, the cells that line the joint. As the researchers discovered in earlier animal studies, synovial cells have a receptor on their surface that's a perfect fit for a particular cytokine, interleukin-1, or IL-1. Like a switch, when IL-1 binds to this receptor, the cell unleashes additional biochemical agents, which in turn cause more local inflammation. As inflammation builds, patients experience progressively worse pain and stiffness in their affected joints.
To block this process, the team sought a way to prevent the main actor, IL-1, from binding to the synovial cells, and hence, setting off the destructive chain reaction that follows. In essence, they needed a way to plug up the receptor and found such a device in a gene encoding the IL-1 receptor antagonist, or IL-1 Ra.
Because it was the first trial of its kind and safety was a key concern, the protocol was designed so that the gene would be delivered to cells that had previously been removed from patients and then, after gene transfer, reintroduced several weeks later after intensive screening and determination of gene expression.
Source:Brigham and Women's Hospital