|by Beth Axtell |
Posted December 7, 2006American scientists Andrew Fire, PhD, and Craig Mello, PhD, shared the Nobel Prize in Physiology or Medicine this year. Although their discovery of a method to control the flow of genetic information seems far removed from the swelling in your knees, Arthritis Foundation-funded researchers are among many in the front lines of using this and other innovative techniques to understand and combat arthritis.
Like most chronic illnesses, the various forms of arthritis have an important genetic component that leaves individuals susceptible to developing the disease. Furthermore, the cells of our immune system and the amount of the various chemicals they release are regulated by the activity of genes. The work of Fire and Mello centered around how the activity of our genes is controlled. All of our genetic information is encoded by the DNA double helix. To produce a protein, the DNA partly unzips and a gene segment becomes a template for the construction of a messenger RNA molecule (mRNA); this is a process called transcription. The mRNA then leaves the cell nucleus and goes to the protein-making machinery of the cell where it is translated into a protein. The control of gene transcription is crucial and determines which proteins are made, and how much.
Drs. Fire and Mello discovered that many genes are naturally regulated by specific small RNA molecules that interfere with the mRNA so that genes are turned off ground-breaking work, silencing genes through RNA interference (RNAi) or through a related technique called small interfering RNA (siRNA) will lead to new treatments for viral infections, heart disease, cancer and even arthritis.
Since the publication of Fire and Mello’s discovery in 1998, researchers around the world have used RNAi and siRNA to study a multitude of diseases. In fact, Paul J. Utz, MD, clinical immunologist at Stanford University and recipient of an Arthritis Investigator Award from the Arthritis Foundation says, “siRNAs are used almost ubiquitously in research laboratories to knock down expression of genes that play a role in inflammation.” Indeed, several Arthritis Foundation-funded researchers have been using these techniques to study the root causes and mechanisms of arthritis and inflammation.
Tamara Alliston, PhD, University of California San Fransisco
Tamara Alliston, PhD, at the University of California San Francisco, is using siRNA to study the molecular pathways that control stem cell differentiation into bone- and cartilage-forming cells. Understanding this process could lead to treatments to prevent osteoarthritis (OA) or maybe even ones that would regrow cartilage. Dr. Alliston says “the siRNA discovery gives us an incredibly valuable tool to investigate the normal molecular mechanisms controlling cell differentiation and how they are disrupted in OA.”
Suneel S. Apte, MBBS, DPhil, at the Cleveland Clinic in Ohio
Suneel S. Apte, MBBS, DPhil, at the Cleveland Clinic in Ohio, uses the siRNA technique to selectively prevent the activities of enzymes involved in the degradation and clearance of cells during remodeling (the natural breakdown and repair of such tissues as bone and cartilage). The information gathered will lead to a more specific understanding of what the enzymes do, help to identify which might be suitable drug targets, and also offer potential treatments for the abnormal remodeling that takes place in joints affected by arthritis.
Qian Chen, PhD, at Brown University in Providence, RI
Qian Chen, PhD, at Brown University in Providence, RI, used the technique to study a particular chemokine (chemical mediator of inflammation). Through this work, his team discovered that blocking the interaction of the chemokine with its receptor could lead to the development of a therapy to protect the cells that build and maintain cartilage.
Mark Ginsberg, MD, at the University of California San Diego
Mark Ginsberg, MD, at the University of California San Diego, uses siRNA to study cell migration within the body – a process that is involved in growth, tissue repair, cancer and inflammation, among others. He and his team are discovering ways to halt the movement of white blood cells to sites of inflammation in arthritis by stopping certain migration-inducing molecules from binding together.
Jessica A. Hamerman, PhD, University of California San Francisco
While at the University of California San Francisco, Jessica A. Hamerman, PhD, used siRNA to uncover how immune system cells are activated when an infection is detected and why certain people’s cells do not deactivate once the injury or infection is gone. She hopes that one day her work will lead to therapy that will tell those immune cells to “turn off” in instances when the body attacks healthy cells, as is the case in autoimmune diseases like rheumatoid arthritis.
Gary S. Firestein, MD, at University of California San Diego
Gary S. Firestein, MD, at University of California San Diego and the 2006 recipient of the Arthritis Foundation’s Howley Prize for arthritis research, is using siRNA technology to study the molecular pathways involved in rheumatoid arthritis joint destruction. Dr. Firestein’s innovative work over the years clearly demonstrates that the greatest progress in medicine often stems from basic science research in chemistry, cell biology, and molecular immunology. He wants us all to keep in mind that research and new technologies “are not just for treatment, but for sorting out the critical pathways involved in the disease process and determining which genes and which proteins are the right ones to target for treatment.”
While these six Arthritis Foundation-funded researchers are using the Nobel Prize-winning discovery to study the basic molecular workings of the body with their eyes on future therapies and potential cures, other researchers around the world are testing the idea that RNAi and siRNA can be sued directly in patients as treatments on their own. In particular, two groups, one based in the US and The Netherlands and the other based in France, are using siRNA as a method of stopping the production of tumor necrosis factor α (a powerful inflammation-inducing chemical). Both groups, using different delivery methods, have had success in treating collagen-induced arthritis in mice. In one study, treatment “markedly inhibited paw inflammation,” and in the other study, treatment “significantly reduced disease incidence and severity.”
Maroun Khoury, MS, the lead author of the French group, says of the future use of the technology, “Approaches using gene therapy appear to hold promise for the specific suppression of immune system targets and long-term expression of therapeutic genes.” Indeed, Khoury continues to explore the many possibilities for clinical applications of RNAi and siRNA, including targeting gene products other than TNFα.
On the other hand, Raymond M. Schiffelers, PhD, the lead researcher of the US and Netherlands group, reminds us that “although siRNA offers promise as a novel therapeutic strategy, it is difficult to handle because the molecule is large, charged, sensitive to degradation by enzymes and needs chemical or physical assistance to pass through cell walls.” He believes that “siRNA is going to be primarily important for elucidating disease pathways, which can contribute to new drugs that specifically affect newly discovered pathways.” This is, of course, just what our Arthritis Foundation-funded researchers are doing, and will continue to do until other discoveries lead them in new directions or until cures for the more than 100 forms of arthritis are found.