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Pulmonary Medicine Research

Cystic Fibrosis Therapeutics Development Center

Principal investigators: Pamela L. Zeitlin, M.D., Ph.D., and Michael P. Boyle, M.D.

Description: We are a part of a network of clinical research centers established at sites with active basic research laboratories focusing on the pathobiology of cystic fibrosis (CF). The Johns Hopkins University clinical research site, with the support of regional affiliated CF clinics, performs multicenter Phase I, II and II trials testing new therapeutics in CF. Current protocols include AAV gene therapy for CF, two new drugs that stimulate alternative chloride channels, new aerosolized defensins and new diagnostic methods.

Molecular Biology of Respiratory Epithelium

Principal investigators: Pamela L. Zeitlin, M.D., Ph.D., William B. Guggino, Ph.D., and Peter J. Mogayzel Jr., M.D., Ph.D.

Description: Dr. Zeitlin and members of her laboratory focus on three areas of basic research: pharmacologic regulation of cystic fibrosis transmembrane conductance regulator (CFTR) protein biosynthesis and trafficking, adeno-associated virus gene therapy for CF and regulation of chloride channel gene expression. Phase I clinical trials studying phenylbutyrate regulation of CFTR expression, AAV CFTR gene therapy to lung and nasal epithelium and MOLI1909 stimulation of calcium-activated chloride channels were developed at Johns Hopkins University based on the molecular bench science.

Dr. Mogayzel’s research focuses on delineating the DNA elements that control the CFTR gene. Understanding the role of these DNA elements in the regulation of CFTR expression will provide insight into the pathogenesis of cystic fibrosis. In addition, incorporating regulatory elements into gene therapy vectors could permit more physiologically appropriate CFTR expression in target cells. His laboratory is using a yeast artificial chromosome (YAC) vector system to create a complete representation of the CFTR flanking DNA. Yeast artificial chromosomes are ideally suited to these studies since they incorporate large fragments of human DNA that can easily be manipulated in yeast before transfer into mammalian cells. Initial studies will utilize chromosome fragmentation to map both positive and negative regulatory elements in the CFTR flanking DNA. Putative regulatory elements will then be analyzed individually in more detail.

Gene Therapy

Principal investigators: William B. Guggino, Ph.D., Pamela L. Zeitlin, M.D., Ph.D., and Michael P. Boyle, M.D.

Description: Our group has been involved in the basic science, preclinical and clinical development of adeno-associated virus (AAV) vectors for gene therapy of cystic fibrosis. Basic vector biology studies include molecular characterization of the mechanisms of long-term persistence of AAV DNA in target cells, the immune response and other host-vector interactions. Preclinical studies in rabbits and primates are used as models for host-vector interaction.

Dr. Guggino has a state of the art vector core facility, which produces high titer, purified AAV and adeno-virus vectors for small-scale in vitro and in vivo experiments. His lab also develops improved packaging and purification of AAV and adeno-virus vector systems. Dr. Zeitlin is conducting a Phase I clinical trial of AAV-CFTR gene therapy in patients with cystic fibrosis. Drs. Zeitlin and Boyle are also exploring the potential of in-utero AAV gene therapy in animal models.

Gene Regulation During Lung Injury

Principal investigator: Sharon McGrath-Morrow, M.D.

Description: The lab is interested in understanding genes that are regulated during lung injury with special emphasis on the effect of injury during postnatal lung development. A major focus of the lab is studying models of bronchopulmonary dysplasia (BPD) and understanding alterations that occur in specific growth factors during lung injury. Previously subtractive hybridization techniques have been used to identify novel and known genes that are involved during lung injury caused by hyperoxia. We are currently studying genes that are involved in growth arrest, injury response and programmed cell death.

Human Research in Aerosol Deposition and Mucociliary Clearance

Principal investigator: Beth L. Laube, Ph.D.

Description: This research focuses on the relationship between aerosol deposition within the human lung and the lung’s response to inhaled allergens, non-specific stimuli, and medications. Gamma scintigraphy provides a method for in vivo quantification of the deposition and removal of radiolabeled aerosol particles in healthy and diseased lungs. Following the inhalation of these particles, scintigraphic images of the lungs can be assessed in terms of deposition fraction, deposition pattern and mucociliary clearance. These image assessments are combined with functional measurements of airway responsiveness to provide a new method for determining the efficacy of a variety of inhaled medications that are administered to the lung as the target organ or through the lung as an alternative to injected delivery. The principles that are basic to this approach are being applied to preventing and treating a number of diseases including asthma, cystic fibrosis and diabetes. Studies are performed in children and adults in the Aerosol and Respiratory Imaging Research Laboratory.

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