Studying how changes in the cystic fibrosis transmembrane conductance regulator (CFTR) create the symptoms of CF is of vital importance. A better understanding of the basic biology of CF, which scientists at Johns Hopkins are investigating through many approaches, will help to reveal targets for drug and genetic therapies.
The CFTR Gene and the Genetics of CF
CF is caused by mutations in the CFTR gene. CFTR expression is highly regulated in a tissue-specific manner. Although the gene was cloned in 1989, and the entire genomic region has been sequenced, the elements that regulate CFTR expression remain unclear. A better knowledge of the regulatory elements that control CFTR expression will aid in understanding CF and in designing more effective drug and genetic therapies. Dr. Peter Mogayzel’s lab is studying how the CFTR gene is regulated.
Dr. Garry Cutting has identified many of the unusual mutations in the CFTR gene that cause CF. More recently, his laboratory has focused on identifying other genes that affect the severity of CF symptoms. Dr. Cutting directs a nationwide research project that is studying twins and siblings with CF to discover genes that may alter the severity of CF lung disease. Dr. Michael Boyle is using a different approach to address the same problem. His laboratory is investigating the expression of all the known genes in CF patients with both mild and severe lung disease in hopes of identifying differences between these two groups. These complementary approaches should enable Johns Hopkins researchers to identify “modifier genes” that affect the severity of CF lung disease.
Elucidating the function of the CFTR protein, its interactions with other components of the cell and how CFTR is processed, is vitally important to our understanding of CF. This work is being undertaken by the laboratory of Dr. William Guggino. Dr. Pamela Zeitlin’s laboratory has focused on how CFTR makes its way through the cell to its surface. This is vitally important because the most common CFTR mutation, ?F508, interferes with the processing of the protein and causes its early destruction. This work has led to promising new therapies for CF. The laboratory of Dr. Sandra Guggino also investigates the trafficking of CFTR through the cell and interactions between CFTR and other ion channels.
Johns Hopkins researchers have pioneered the creation of adeno-associated virus (AAV) gene therapy vectors and their introduction into clinical trials. Ongoing research in the laboratories of Drs. William Guggino and Pamela Zeitlin is aimed at unraveling the barriers to effective gene therapy and refining new vectors. Dr. Anne Fischer has been investigating the safety and effectiveness of newly created AAV vectors in animal models, key to creating a viable vector for human studies.
Microbiology of the CF Airway
The emergence of resistant bacteria and their effect on the lung function of CF patients is being studied by Drs. Christian Merlo and Noah Lechtzin. The analysis of data collected in the CF Foundation registry is leading to a better understanding of the role of infection on the health of CF patients.
Mucociliary clearance or MCC is a major defense mechanism that protects the lungs from infection. Inhaled bacteria are trapped in the mucus that lines the airway and then transported out of the lungs by the beating of cilia, small hair-like structures on the surface of airway cells. The thick, sticky mucus that is present in the lungs of CF patients leads to abnormal MCC. Dr. Beth Laube is studying the role that MCC plays in the colonization of the CF airway. These studies are being performed in mouse models of CF as well as in patients with CF.
CF patients often metabolize drugs in unexpected ways. Pharmacist Carlton Lee studies the way CF patients metabolize commonly used drugs such as antibiotics.