Few scientists are as familiar with gene therapy's promises—and obstacles—as HHMI investigator Katherine A. High, who served last year as president of the American Society of Gene Therapy. Once touted as a revolutionary breakthrough, gene therapy has endured intense scrutiny since 1999, when a teenager died in an experiment. Nevertheless, High remains a vocal advocate for fully exploring the field's possibilities. Her own research involves development of gene-therapy techniques to treat hemophilia. She is an attending hematologist at the Children's Hospital of Philadelphia and William H. Bennett Professor of Pediatrics at the University of Pennsylvania School of Medicine.
HHMI: GENE THERAPY IS OFTEN CALLED A MIXED SUCCESS. HAS THAT STATUS BEEN DEMORALIZING FOR PEOPLE IN THE FIELD?
KH: Gene therapy is as complicated a therapeutic idea as any that researchers have attempted, but if you're intensively involved in the field, you don't feel despair. We're solving problems every day. Five years ago, we could only use gene therapy to cure diseases in mice. Today, we're curing diseases in dogs and cats—and even beginning to treat humans. Researchers in Milan have used gene therapy to successfully treat six kids with a form of severe combined immune deficiency known as ADA-SCID. And China approved the first commercial gene-therapy product, to treat cancerous tumors of the head and neck.
For perspective, consider the history of novel monoclonal antibodies for the treatment of cancer. When I was in medical school in the 1970s there was a lot of hype about them, followed by widespread disappointment during the 1980s when newspapers announced that all the clinical trials were failing. The field then dwindled to fewer scientists, and this core group worked hard to overcome hurdles. Today, monoclonal antibodies are considered a great success, though it's easy to forget that this success was 30 years in the making.
HHMI: WHAT ARE THE BIG CHALLENGES IN GENE THERAPY NOW?
KH: Immune response to the viral vector is one big challenge. Think of this vector as an envelope and the gene product being delivered to the patient as the letter inside. Too often, that patient's immune system rejects the envelope, and the letter within is never even read. So we're exploring ways to create transient immunosuppression—to shut down a patient's immune system just long enough for the viral vector to degrade, thereby allowing the body full exposure to the gene product inside.
Another challenge is immune response to the gene-transferred product itself. In this regard, one interesting strategy is to ask: Can we exploit nature's redundancy? Traditionally, gene therapy meant delivering a healthy gene to replace a mutated one. But now we often ask whether we can achieve the same biochemical effect through a different route.
Hemophilia offers one example. The body has at least two biochemical pathways that produce several important blood-clotting factors. The first pathway produces factor VIII and factor IX, but if a hemophilia patient is missing one of them, we don't necessarily try to replace it. Therapy might instead rev up the second biochemical pathway, which relies on factor VII, by generating extra amounts of that factor, which the patient's immune system will accept.
Photo: Sean Kernan