Jeffrey Wine, Ph.D., of the Cystic Fibrosis Research Lab at Stanford University, opened his talk on a hopeful note, pointing out how far research into the cystic fibrosis gene defect has come since the mid-1980s and how much more we know today.
In his update on basic research, Dr. Wine pointed out that we now know that CF is caused by mutations in the gene for Cystic Fibrosis Transmembrane-conductance Regulator (CFTR), a complex protein that forms chloride channels in cell membranes. New information is available on all aspects of CFTR physiology. The number of cellular factors that regulate CFTR is large, and more is now understood about how they change the way the CFTR channel opens and closes. Less is known about how CFTR is made and moved through the cell to take up residence in the cell membrane. There is evidence that CFTR moves in and out of the membrane, but the factors controlling this are poorly understood. Regulation of this membrane is spectacularly complicated and there are many ways this channel can go wrong.
This secretion and absorption of chloride, and resulting changes in the amount and composition of fluid in exocrine organs, continues to be the dominant, unifying hypothesis in CF research. In the lungs, evidence is consistent with the importance of secretions from glands and special cells lining small airways. CFTR is not found in lung airways, but in the surface of small airways and in glands. Altered secretions at a very early stage might predispose the lung to inflammation, even before infection starts. Dr. Wine suggested several other interesting hypotheses on how these chloride conductance imperfections could lead to lung disease. However, new animal models are needed to thoroughly test models of CF lung disease.
A great deal has been learned from the existing mouse model. Most importantly, it has been shown that any organ containing alternate chloride channels is spared the ravages of CF disease. Having higher amounts of these channels in some organs may explain milder CF symptoms in certain patients who have "severe" CF mutations.
Dr. Wine also addressed updates in applied CF research. He noted that pharmacological approaches to making D F508-CFTR work better are having some success in the laboratory. Recently, a mouse model for CF caused by D F508-CFTR has been developed, and this should speed research on this approach.
Strategies that ameliorate lung disease without attempting to reverse the basic defect have also received considerable attention, most recently, DNase (also known as Pulmozyme). Other developments attempt to blunt the inflammatory process at many levels, and on this front, the most important new information is that epithelial cells themselves are major components of immune responses in the lung. There is also increasing evidence that CFTR influences many cellular processes in addition to, or secondary to, its role as a chloride channel, and some of these have also received attention as therapeutic targets. For example, CFTR seems to inhibit sodium channels and also cell surface receptors for bacteria.
Dr. Wine ended on a promising note, concluding that gene therapy remains the most powerful potential approach. He moderated the heightened excitement of the past few years, noting some of the disappointments of the last year, including reinterpretation of earlier positive results and numerous new barriers encountered to potentially effective treatments. He asserted that to achieve an acceptable rate of progress in this area, research requires better understanding of fundamental principles of the disease and of lung physiology, and better model systems with which to work.
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