Translational medicine is all about moving therapies from the research laboratory to the patient. Making that transition happen is a major focus of the division of Pediatric Pulmonology. One of the most active areas for translational medicine within the Center is at the CF Clinic, where a robust clinical trial program usually has around 10 to 15 trials going on at any one time.
Our research program ranges from clinical, translational, biologic and health outcomes. Our clinical research program entails over 50 active clinical research protocols, 6 full-time research staff, and includes both investigator-initiated and industry-sponsored, multi-center studies are ongoing with patient enrollment underway. Translational projects include optimization of sweat chloride testing, creating knowledge surrounding the microbiome of the lung, imaging strategies for early lung disease, and anti-oxidant strategies for lung transplant and cystic fibrosis patients. Our basic laboratory research program use state-of-the-art approaches to investigate the mechanisms underlying normal lung development, perinatal pulmonary adaptation, gene regulation, pulmonary injury and repair, surfactant homeostasis, antioxidants, transcriptional factors, and regulation of pulmonary vascular tone. Investigators work on the pathogenesis of both common and rare lung diseases. The overarching goal of the basic science program in the division is to improve our understanding of the cellular processes and genes that regulate lung development and homeostasis. The overall goal of the program by being concomitantly engaged in basic, clinical, health outcomes, and translational research is to develop meaningful knowledge to motivate the therapies to address neonatal and pediatric lung diseases.
Carlos Milla, MD, director of Lucile Packard's Cystic Fibrosis Clinic, has devoted much of his energy over the years to developing therapies for cystic fibrosis, a disease that most often strikes children when they are quite young. The life expectancy of CF patients has been substantially extended in recent years owing to research that has led to better anti-infective drugs, earlier diagnosis, and improved understanding of nutritional needs. A crucial step in getting new therapies spawned by scientific discoveries to patients is the clinical trial.
Jeffrey Wine, Ph.D directs the cystic fibrosis (CF) Research Laboratory at Stanford. Dr. Wine conducts basic and applied research designed to ameliorate CF disease. CF is caused by the loss or malfunctioning of the CFTR anion channel, which is important for fluid transport, salt absorption and pH regulation in many epithelia. The Wine Lab seeks to understand how lost CFTR function causes the lungs of CF patients to be so susceptible to infection—this work has focused on secretion by airway glands and on mucociliary transport. We have also developed and are employing assays based on sweat gland secretion as sensitive in vivo biomarkers for CFTR function in humans. For both projects, we have developed optical methods that accurately track secretion rates from single glands, and we use pharmacological methods to dissect pathways that depend upon CFTR. Through this work we have been able to identify a number of fundamental defects in the CF glandular secretions, and can use these measures to quantify responses to CFTR-modifying drugs. Our work with airways has suggested treatment strategies that can help minimize CF airways infections.
NAC, short for N-acetyl cysteine, and has been used successfully in treating a number of diseases including HIV/AIDS and pulmonary fibrosis, which scars the lungs
Carol Conrad, MD,initiated the NAC study. Results of the new treatment look promising for children with CF.
Lung infections and the resulting inflammation are a persistent problem for CF patients, with the inflammation opening the door for additional infections to take hold. "It's a vicious cycle of inflammation and infection," says Zoe Davies, PNP, pulmonary nurse practitioner and research coordinator.
One reason inflammation is such a problem in CF is that the white blood cells that combat inflammation are missing a critical ingredient, an antioxidant protein called glutathione, the lack of which renders them ineffective. The body tries to compensate for that deficit by producing even more white blood cells, which only inflames the lungs further.
Lung Development Research
Many pediatric lung disorders are currently poorly understood at the cellular level. Understanding the development and function of individual cell types within the lung will provide novel therapeutic approaches. Christin Kuo, MD, initiated a study using genetic in vivo approaches to understand lung neuroendocrine (NE) cell development at single cell resolution, revealing a novel mode of epithelial migration. Pulmonary neuroendocrine (NE) cells are specialized airway epithelial cells with sensory, neurosecretory, and stem cell functions. Many NE cells are localized at branchpoints in highly innervated clusters of called neuroepithelial bodies (NEBs) which are increased and abnormally distributed in many pediatric and adult respiratory diseases. Her lab is using single cell whole transcriptome analysis to identify candidate molecules guiding the formation of NE cell migration and innervation to form specialized sensory and secretory structures within the lung to understand how abnormal regulation or execution of this developmental program perturbs respiratory function in neonatal lung diseases or how the normal program may be inappropriately re-activated later in life such as in NE cell tumors.
Collaborations Speed Progress
Partnerships are a vital component of the effort to move therapies from theory into use with patients. The Division of Pulmonary Medicine is really based on the idea that the research should be very broad and interdisciplinary," says Richard Moss, MD , adding that the ability to engage in those kinds of collaborations at Stanford is one of the great strengths of the Clinic. When researchers with a wide range of specialties can join forces to develop a therapy for a disease, it can make a huge difference in speeding the work to the stage where it can help sick children.
The potential for that sort of cross fertilization of ideas is precisely what lured David Cornfield, MD, director of the Center, to Packard Hospital. "The sort of confluence that goes on between the clinical and the research arenas here is perfectly well matched for the sort of care that goes on in CF related disease," says Cornfield, whose own research focuses on pulmonary hypertension.