THE CUTTING EDGE: Designer Genes

Treatment at the new gene therapy clinic starts small, but makes big headlines On September 3, James Wilson made international headlines when he implanted a gene into a 32-year old woman with cystic fibrosis. Ten days later the New Jersey woman returned to her normal routine at work. And although the woman's treatment will not eliminate her lung disease, Wilson is confident that within his test tubes lies the cure to many lethal genetic diseases. In March, Wilson came to Philadelphia to head the University's newly formed Institute for Human Gene Therapy – the only center of its type in the nation. Wilson, 38, has been searching for an effective way to translate the laboratory genetics into medical cures since he earned his Ph.D. at the University of Michigan in 1984. At that time he studied Leschnyhan syndrome, a form of cerebral palsy that causes patients to mutilate themselves. The disease has been isolated to a single gene, which Wilson studied at the molecular level. But Wilson said knowing the structure is not sufficient. His center's aim is to discover how to implement that knowledge. Wilson brought 20 researchers and assistants from the University of Michigan to help in his study. "I was frustrated by the fact that the knowledge we gained had no effect on patients," Wilson said. "We could tell the parents of the patients that we knew what was wrong but they would ask how it [the knowledge] could help and we had no reply." The cystic fibrosis case demonstrates that the process between understanding genetics and treating patients is long and complicated. Cystic fibrosis is the nation's most common lethal inherited disease. Patients with this disease lack a gene that prevents the body's flow of salt and water that is responsible for preventing a dangerous accumulation of mucus in several organs, including the lungs. The experiment began in 1989 when University of Michigan researcher Frances Collins cloned the gene responsible for cystic fibrosis. Next, Wilson and his research team worked to reconstruct the normal gene and developed models to insert it into a human. After many trials Wilson discovered that the healthy gene could be carried into the body by a virus. The adenovirus, which commonly causes respiratory problems, was determined to be the best vehicle to transport the healthy gene. But at this point Wilson came to a stand still since, unlike other diseases, no good animal models have been developed for cystic fibrosis. Wilson ultimately decided to extract diseased human lung tissue and transplant it into a mouse. Wilson said he was lucky in that diseased lung tissue was readily available because the patients often need lung transplants. At this stage, the gene is inside a virus which is inserted into diseased lung tissue that will be transplanted into the laboratory animal. But while the procedure was successful in treating the mouse's artificial disease, researchers were skeptical as to whether or not this treatment would be safe on humans. In order to protect the patients, Wilson conducted tests on baboons to determine the safe dosage range. Once this had been determined, he solicited volunteers for the trial and selected 20 people who have been divided into two dosage groups. "I am in awe of her courage to participate and to be the first," Wilson said of the New Jersey woman. "[The experiment] is a paradigm in molecular medicine." She is the fourth person in the U.S. and the first in the Philadelphia area to receive this type of treatment. This first phase, however, is not specifically designed to cure the patients, Wilson said. Rather, it will supply the research team with vital data on human response to genetic therapy that will guide the actual study. The woman will not be cured because only a small portion of her lung was treated. "After completing the first stage of therapy on the New Jersey woman, I was delighted to see that there were no complications," he added. "I was more determined to move forward even more aggressively so that I could say to the woman when she comes back to the hospital that we have a cure." The patient received the gene through a bronchoscope which was led through her mouth, down her throat and into an isolated area of the left lung. The instrument served as a funnel to transport a saline solution which contained millions of adenovirus particles carrying copies of the engineered normal cystic fibrosis gene. Wilson warned that because doctors are very cautious in this type of research, they start with a single delivery of the gene in a low dosage and observe. Wilson said that once he is certain that the patient does not experience any adverse effects, he will increase the dosage slightly for the next group. Wilson hopes that the 20 patients will be sufficient to determine an effective dosage. Almost one month later, the woman – whose name has not been released – is now living at home and says she is feeling well. She has not yet experienced any adverse reactions to the treatment. "What drives us as doctors is seeing patients with lethal diseases and knowing that there is nothing we can do to directly cure them," he said. But, Wilson and his research team will have to wait and continue to monitor the tissue in her lung to see if the gene has transferred. They are unsure how long it will take. Wilson said that because of the experiment's success so far, he plans to continue to administer the gene through a virus. It will be applied to three general groups – children born without immune systems, children born with inherited gene defects of high cholesterol and patients with cancer. "There is no doubt in my mind that gene therapy will have a role in cystic fibrosis in the future," Wilson said. "The actual virus [for transport of the gene] we do not know yet." Wilson said that in the future, the gene therapy system will most likely be specialized for each disease. "But the timespan for a cure will be a matter of years, not decades in my opinion," Wilson said. Moreover, Wilson said, the overall cost of gene therapy will be cheaper in the long term. "Compare the cost of other drugs that must be taken daily, often three times a day, for a lifetime to the cost of the singular or few gene therapies."