Dr. Katherine High, University of Pennsylvania School of Medicine and Children's Hospital of Philadelphia, gave a topical lecture entitled, "Gene Transfer for Genetic Disease: Hemophilia as a Model for Prospects and Problems," at the American Association for the Advance of Science Exposition on February 15, 2002. This article briefly summarizes Dr. High's lecture and explains its key points.

What is gene therapy?
The idea behind gene therapy is to give cells a gene which functions in a normal way in order to override or replace a gene that is functioning abnormally. In hemophilia B the gene which controls the production of a clotting factor (Factor IX) malfunctions, and because of that boys and men with the disease can't form enough blood clots to stop bleeding when it occurs. The goal of gene therapy in this case would be to replace the part of the gene that is not working correctly so that sufficient amounts of Factor IX would be produced in the body.

How it's done
Replacing the defective gene part, however, is not (yet) a simple process. There are three parts involved in gene transfer:

• The vector - think of it as the "envelope" that will carry the new gene part into the body's cells
• The transgene - the new gene part, the "letter" in the envelope
• The target cell - where the new gene part is supposed to go, the "mailbox" for the letter

Viruses are very good at getting inside the body's cells, so researchers "deactivate" viruses (take out the disease parts) and use them as the vector (envelope) to carry the transgene. Dr. High's research team has successfully used adeno-associated virus (AAV) vectors to carry the hemophilia B transgene.

Mice, dogs, and men
One of the problems researchers who work with mice have is how to apply the research results obtained to human beings, since people are much larger animals and the human body may or may not respond in the same way as a mouse. Dr. High's team decided to work with dogs with hemophilia B, since dogs are larger animals than mice and it might be easier to transfer the knowledge gained to people. The results of the research with dogs was encouraging: after injections of the transgene the dogs' blood levels of Factor IX rose, meaning the transgene "took."

The next challenge for the research team was calculating what they thought would be a therapeutic dose for a human being. Of the first men with hemophilia B given the gene therapy, the results were mixed: some of the men had slightly increased levels of Factor IX and some showed no change. (The goal was for the subjects to have levels of Factor IX >1% of normal.) Dr. High's team continues to test dosages to try to find the correct one that will produce a consistent result.

Potential of gene therapy
Dr. High emphasized that in order for gene transfer to be successfully applied to diseases, there must be a careful selection of disease targets, a multidisciplinary research team, and a profound understanding of the pathophysiology of the disease being investigated. If these conditions are present--as Dr. High's work with hemophilia demonstrates--gene therapy holds tremendous potential for relieving, and possibly preventing, disease.

Information for this article was taken from your Guide's notes from the lecture. Dr. Katherine High may be reached by email at the University of Pennsylvania School of Medicine at high@email.chop.edu.

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