Children's receives one of only two national pediatric rheumatology training grants

nding what causes pediatric rheumatic diseases and how to cure them.

Dr. Hirsch and his team are using DNA micro arrays, or "DNA chips," to examine the gene profiles of both mice with induced arthritis and JRA patients to identify the genetic characteristics of the disease. Of particular importance is learning which genes are being over-expressed and which are being under-expressed in a particular patient at a specific point in time.

These gene expression profiles will help identify new targets for therapy and might someday help doctors more accurately diagnose JRA, predict outcomes and even determine which therapies individual patients are most likely to respond to. Gene expression analysis has already led to the discovery of several genes that appear to be involved in the destruction of the joint itself.

In another project, delivering gene therapies to diseased synovium of children with JRA is being investigated to improve the safety and effectiveness of new biologic drugs -- such as etanercept -- that dramatically ease disease symptoms.

"The concept is that the gene becomes the drug," Dr. Hirsch says. "We are delivering the gene to the synovium itself. Synovial cells then incorporate it into their genetic machinery and begin to make the protein locally."

The goal is to achieve steady-state levels of short-lived biologic agents in the diseased joints of patients and to eliminate systemic delivery. This, in turn, lessens the risk of possible side effects associated with the tumor necrosis factor-blocking drugs, whose long-term effects on the body's tumor surveillance capabilities is unclear.

Not only is Dr. Hirsch searching for the cause of JRA in the laboratory, he also is recruiting some of the best researchers and clinicians to join him in paving the way to more effective therapies.

"Although we are interested in the basic biology," Dr. Hirsch says, "everything we do is really focused on how to apply t

Contact: Melanie Finnigan
Children's Hospital of Pittsburgh

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