Research published in The New England Journal of Medicine reported a long-awaited breakthrough in the fight against cancer.

Through the use of gene therapy, two patients who were dying of leukemia were seemingly cured of the disease. The results occurred after immune cells called T-cells were removed from the body, genetically engineered to attack the cancer and returned to the body, where they multiplied 1,000-fold, rapidly destroying more than two pounds of tumors in each patient. A third advanced leukemia patient went into partial remission-a lot, but not all, of the cancer was destroyed.

The research was heralded as a "huge accomplishment." Do these dramatic results mark the beginning of significant advances that may occur with other diseases?

For answers, we spoke with James Wilson, MD, PhD, one of the nation's leading experts on gene therapy…

  • What is gene therapy? Gene therapy is a new approach for preventing, treating or curing diseases through the alteration of defective genes. Most people know that genes, which reside within the nucleus of each cell, are sequences of DNA that determine a specific trait, such as whether you have blue, green or brown eyes. There are more than 30,000 genes that make us human and make each human unique.

Genes provide the instructions for the manufacture of proteins that allow the body to function. But if genes mutate, they provide faulty instructions. Mutated genes play a role in virtually every disease. This, of course, includes so-called "genetic diseases" such as sickle-cell anemia and muscular dystrophy, which are caused by an inherited defect in a single gene, but also certain cancers such as leukemia.

Gene therapy attacks various types of disease at their roots—inserting into the cell a normal copy of the gene, which overrides the genetic mutation that causes disease.

  • How is gene therapy different from drug therapy? When a doctor gives a drug, it treats the symptoms of the disease, not the root cause. And you must take the drug every day (or several times a day)-sometimes indefinitely.

With gene therapy, a normal gene is administered usually via injection or intravenously—sometimes multiple times—to targeted cells. Once there, it should stay active for a very long time and, in some cases, the rest of the person's life, guiding the creation of healthy cells to replace the defective ones.

  • When did gene therapy start? In the 1980s, scientists began inserting genes into cells in petri dishes. Inserting genes into cells within the human body has proven quite difficult, however.
  • Have those challenges been solved? The big breakthrough came when scientists realized that the shell and contents of a virus could be used to transport a normal gene into a cell. They engineered the simple genetic sequence, or genome, of a virus, removing two or three viral genes (thereby rendering them harmless), stitching in corrective human genes and then putting this encapsulated vector into the body. The genes were also engineered to seek out and find specific types of cells, such as lung, heart, liver or brain cells.
  • What are the risks of gene therapy? The biggest problem is when the body recognizes the vector as a dangerous virus and mounts an immune response that can lead to inflammation, cancer or even death. Before we recognized this problem, a young man with a genetic disease of the liver died unexpectedly in a clinical trial of gene therapy in 1999. Another problem occurs when the vector inserts its genetic payload into areas of the chromosome that inadvertently activate cancer-causing genes. Needless to say, these issues prompted a search for safer vectors-and it has taken several years.
  • Have safer vectors been found? Yes, progress has been made. The Gene Therapy Program at the University of Pennsylvania discovered and developed for gene therapy new members of an obscure family of viruses called adeno-associated viruses (AAV). Over the last few years, we have sent these vectors to approximately 1,000 scientists at 450 institutions in 30 countries and they are now used as the principal vectors in almost all studies on gene therapy. The vectors have proven to be remarkably effective and safe, although we are still encountering and working to solve remaining problems of immune response. To prevent the inadvertent development of cancer, scientists are developing vectors that persist without perturbing our chromosomes in ways that may be harmful.
  • What are the most promising areas for gene therapy? The most promising are the lethal genetic diseases, such as muscular dystrophy, hemophilia and Tay-Sachs disease—conditions for which there really aren't any other effective therapies. Gene therapy works well for these diseases because they are caused by a single defect in a single gene, and we know what and where that gene is.

Gene therapy is progressing in clinical trials focusing on several other diseases, presumably caused by multiple mutated genes. These diseases include Parkinson's and age-related macular degeneration.

And as the research on leukemia shows, gene therapy may also attack cancer. It works not by targeting cancer cells directly, because they are genetically diverse, but by engineering immune cells with a vector that makes them more efficient at recognizing and killing tumor cells.

  • Can my doctor prescribe gene therapy? Gene therapy is still in clinical trials. During the next year or two, I expect to see the successful completion of Phase III clinical trials and the introduction of approved gene therapy products for genetic diseases, such as an inherited form of high lipids, hemophilia and inherited blindness. In the next decade, we may well see commercial gene therapy products for diseases such as cancer and Parkinson's.
  • What's the best way to find clinical trials that use gene therapy? Check the National Institutes of Health site, www.clinicaltrials. gou. Search the key words "gene therapy" to see which of the more than 2,600 trials involving gene therapy are actively recruiting patients.

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