Gene therapy for arthritis is feasible and safe, reported Monday the researchers who conducted the world's first such clinical trial on patients with advanced rheumatoid arthritis.

The results, published in this week's online edition of the Proceedings of the National Academy of Sciences (PNAS), indicate that introducing a new gene has the potential to block the destructive inflammation process that takes place within arthritic joints.

At a time when setbacks have cast doubt on the future of gene therapy, the results also provide assurance that it can be performed without causing harm to patients, said the scientist.

The clinical trial, which was conducted at the University of Pittsburgh School of Medicine between 1996 and 1999, involved nine women who had genetically modified cells injected into their arthritic knuckles and marked the first time a gene was introduced into a human joint.

The results showed that successful gene transfer can target joint inflammation, opening the door to the development of improved gene-based therapies for both rheumatoid and the more common osteoarthritis that together affect millions in the world.

In this study, scientists used a vector, a replication- defective retrovirus called Maloney Murine Leukemia Virus, to deliver new gene into the patient's joint. With safety a key concern, they have been checking the patients frequently for five years and found no evidence that the virus has become capable of replication in patients.

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.

Synovial cells have a receptor on their surface that is a perfect fit for a particular cytokine, interleukin-1 (IL-1). 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 IL-1 from binding to the synovial cells and hence setting off the destructive chain reaction. They found such a device in a gene encoding the IL-1 receptor antagonist, or IL-1 Ra, to stop IL-1.

According to the results, joints treated with the genetically modified cells exhibited high levels of IL-1 Ra, indicating successful gene transfer. Clusters of cells that expressed large amounts of the gene were present on the surface of the synovial tissue and produced significantly less inflammation-provoking substances.

In their animal studies before the clinical trial, the researchers had noted that a small percentage of injected cells could escape to other tissues within one week. But five years later, they have seen no evidence that these genetically modified cells have caused any adverse events in their nine patients.

Although this approach did prove safe and was able to confer gene expression within arthritic joints, the researchers noted that it was time-consuming and expensive.

Now they would advocate a better approach, introducing the gene directly to affected tissue with an adeno-associated virus (AAV) as the vector.

AAV appears to have a good safety profile and facilitates more extended gene expression, the researchers said, hoping to conduct new clinical trials in both osteoarthritis and rheumatoid arthritis using AAV to transport the gene.

Source: Xinhua