Cystic Fibrosis is caused by inherited mutations in a gene called the Cystic Fibrosis Transmembrane Regulator (CFTR). The mutations, or mistakes in the gene, prevent CFTR from operating properly. Normal CFTR helps to control salt and water movement in the moist linings of the respiratory tract and other affected organs. Mutated CFTR fails to operate properly and causes those moist linings to become more dry. This, in part, leads to the thick mucus which helps cause infections in the lung and the sinus.
Gene therapy for CF is a process by which the normal CFTR gene is put into cells already containing the mutated, malfunctioning CFTR. We use a virus called adeno-associated virus (AAV), which does not normally cause any human diseases, to help put back the normal CFTR. Cells actually become "infected" with normal CFTR. This is done by first taking out the normal virus genes which allow it to reproduce, or make additional infectious copies of itself. The normal CFTR gene is inserted into the virus. The new virus is called an adeno-associated virus mediated CFTR vector (AAV-CFTR). This virus can then enter CF human cells and instruct them to make normal CFTR. Since AAV-CFTR does not contain the main virus genes, it is unlikely to produce an immune response. Other vectors that have been used to attempt gene therapy of CF include adenovirus and liposomes (see CFRI News Spring and Fall 1995 issues). So far, these methods have proved inadequate because of the immune response and low efficiency, respectively.
Although the life-threatening complications of CF occur in the lungs, we use the maxillary sinuses to test AAV-CFTR gene therapy. Why? The sinus disease of CF patients is similar in many ways to lung disease. CF sinuses have similar physiology, including malfunctioning CFTR, similar infections, especially with Pseudomonas aeruginosa colonization, and similar disruptions in clearance of secretions. Gene therapy may be useful in its own right in the sinuses in order to quell sinusitis symptoms like headache and post-nasal drip. In addition, the sinuses are easier to access than the lungs, safer for the patients, and yet still allow us to study how gene therapy affects the clinical course of CF by looking at sinusitis. If AAV-CFTR proves effective in treating CF sinusitis, then it is likely to also prove effective in treating CF lung disease. Using the sinuses is also advantageous because the opposite, untreated sinus can be used as a control. Although some types of gene therapy have been shown to make normal CFTR in patients, no CF gene therapy has been demonstrated to have any effect on the clinical course of the disease.
Our study involves the collaborative efforts of many scientists and physicians from the Stanford University medical research community, including myself, Phyllis Gardner, M.D., Mary Lynn Moran, M.D., Anna Messner, M.D., Richard Moss, M.D., and Jeffrey Wine, Ph.D., among others. In addition, this effort also involves scientists at Targeted Genetics Corporation and the Johns Hopkins Medical Institutions. We are especially grateful to the patients participating in these studies. We have treated four patients with low doses of AAV-CFTR and we plan to treat more patients at higher doses. Results from the study will remain preliminary until we enroll additional patients. Gene therapy remains a promising potential treatment for CF, but will require much more research and testing before it becomes a reality for all patients with CF.
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