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, which is highly regulated in a tissue-specific manner. Understanding the relationship between mutations in the CFTR gene and clinical symptoms is vitally important. 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 and environmental factors 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. Additionally, along with Dr. Patrick Sosnay, Dr Cutting has been studying the function of rare CFTR mutations and has been instrumental in the creation of the CFTR2 database, which categorizes these mutations.
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. Liudmila Cebotaru’s and Dr. Pamela Zeitlin’s laboratories have focused on how CFTR makes its way through the cell to its surface. This is vitally important because the most common CFTR mutation, F508del, interferes with the processing of the protein and causes its early destruction. This work has led to promising new therapies for CF.
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 Dr. William Guggino and Dr. Liudmila Cebotaru is aimed at unraveling the barriers to effective gene therapy and refining new vectors. Dr. Liudmila Cebotaru 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. Natalie West 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. Dr. Michael Boyle is studying therapies to eradicate methicillin resistant Staphylococcus aureus from the airways 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 individuals with CF.
Individuals with CF often metabolize drugs in unexpected ways. Pharmacist Carlton Lee studies the way individuals with CF metabolize commonly used drugs such as antibiotics.