Research in Diseases, Disorders, and Health Conditions
Chronic Diseases and Organ Systems
Cystic fibrosis (CF) is an inherited, autosomal recessive disease of the secretory glands, including the glands that make mucus and sweat. It is caused by mutations in the gene for CF transmembrane conductance regulator (CFTR), which codes for an ion channel. CF mostly affects the lungs, pancreas, liver, intestines, sinuses, and sex organs. Mucus becomes thick and sticky, accumulates in the lungs, and blocks the airways, thereby rendering them susceptible to repeated bacterial infections that can severely damage the lung. Respiratory failure due to bacterial infection is the most common cause of death in people who have CF. Mucus blockage of the pancreatic ducts can cause vitamin deficiency and malnutrition. In addition, CF patients lose large amounts of salt when they sweat, which can lead to dehydration, increased heart rate, tiredness, weakness, decreased blood pressure, and heat stroke. Improved treatments have led to a dramatic increase in the life expectancy of people with CF, now averaging about 37 years of age, but some are living into their 40s, 50s, or older. As more and more people with CF reach adulthood, however, it has been discovered that about half will develop cystic fibrosis related diabetes (CFRD), an unusual form of diabetes that can lead to deterioration of lung function and a poorer prognosis.
Over the past two decades CF research has greatly improved our understanding of CFTR regulation at the molecular level, demonstrated the functional consequences of CFTR defects at the cellular level, and led to the development of several new experimental therapies. Many abnormalities have been characterized in CF, including defects in ion transport, innate immunity, airway hydration or clearance, and excessive inflammation, but which of these factors is key to morbidity and mortality and how these abnormalities are interrelated remain unknown. Current research is focused on development and characterization of animal/cell models to understand early CF disease pathogenesis; identification of genetic and environmental modifiers of CF; molecular phenotyping of CF lung disease, liver disease, and CF-related diabetes; exploration of microbiome diversity in the CF lung and GI tract, and its role in the progression of lung and digestive diseases; understanding of mechanisms regulating infection, inflammation, and remodeling and mechanisms regulating mucociliary clearance and airway surface liquid homeostasis; and development of therapeutic and preventative efforts to forestall CF disease onset and progression.
Current CF treatments are focused on relieving symptoms and improving quality of life. Direct modulation of the underlying pathophysiological mechanisms of CF is a long-term therapeutic goal.
Current CF treatments are focused on relieving symptoms and improving quality of life. Direct modulation of the underlying pathophysiological mechanisms of CF is an attractive long-term therapeutic approach. In a recent randomized, double blind, placebo-controlled, multicenter trial, a new oral drug, VX-770, was found to be safe and to confer considerable improvement in the function of the defective ion channel in people with an uncommon CFTR mutation. A subsequent phase III trial published in 2011 demonstrated dramatic benefit from the drug in these patients; 260 the drug was approved by the FDA in 2012, and is now available to patients, marketed as Kalydeco™. Ongoing efforts include taking similar approaches to identify medications that may benefit patients with the more common CFTR-deltaF508 mutation.261
Recent laboratory studies using cells that have the same genetic defect found in most patients with CF showed that the drug suberoylanilide hydroxamic acid was able to reprogram the lung cell environment to correct the CF abnormalities. Further development of novel targets for small molecule “correctors” of CF may lead to restoration of the defective ion channel. Other recent research suggests that modulating the activity of the cell’s protein quality control machinery may be an important strategy for helping boost activity of the channel in some patients.262
Unlike type 1 diabetes, the insufficient insulin production in CFRD stems not from an autoimmune attack on the pancreas, but rather from a progressive loss of pancreatic function similar to what is seen in type 2 diabetes. And while CFRD involves insulin resistance and has other metabolic and genetic similarities to type 2 diabetes, it is not associated with being overweight or obese. Indeed, a serious concern regarding CFRD is that it tends to induce weight loss in CF patients, who are often underweight already. However, it was unclear whether people with the disease were likely to face the same array of other serious complications endured by people with more common forms of diabetes. Thus, many health care providers were therefore reluctant to prescribe insulin for CFRD, because no one knew whether insulin, or indeed any drug used to treat other forms of diabetes, would help people with CFRD to be healthier. Recent research demonstrated that insulin therapy indeed can help people with CFRD maintain their body weight, improve lung function, and feel healthier.263
Although the genetic cause of CF has long been understood, unaccounted for was the wide range of symptoms observed in CF patients, even among those who share identical CFTR mutations. Investigators found regions on chromosomes 11 and 20 that can modify the effects of the CFTR mutations by ameliorating or exacerbating the disease as it progresses. They tested DNA from 2,464 CF patients, then replicated their findings and confirmed their results in 973 additional CF patients. Better understanding of how CFTR mutations are modified by regions of chromosomes 11 and 20 could lead to improved therapies tailored to the individual genetic profiles of CF patients.264
Bacterial clusters (known as biofilms) living in the lungs of CF patients are highly resistant to killing by antibiotics. A key cause of resistance is that bacteria become starved for nutrients during infection. It was previously thought that as the starved cells stop growing, the cellular functions targeted by antibiotics are no longer active, reducing the effectiveness of the drug. These findings suggest new approaches to improve treatment for a wide range of infections and restore antibiotic efficacy to available drugs.265
The mechanistic link between missing CFTR and hyperabsorption of sodium in airway epithelia in CF has remained elusive, but recent findings indicate that when the epithelial sodium channel (ENaC) is associated with normal CFTR, it is protected from proteolytic cleavage and activation. In contrast, the most common form of mutant CFTR fails to protect ENaC from proteolytic cleavage and stimulation. These results indicate that CFTR down-regulates sodium absorption by limiting proteolytic cleavage of ENaC.266
Researchers recently produced pigs and ferrets with the same genetic mutation that causes most CF in humans. Pigs represent an attractive model for the study of CF lung disease, because their lungs share many anatomic, biochemical, and physiologic features with the human lung. During their first six months of life, CF pigs spontaneously developed lung disease, including the hallmark features of infection, inflammation, remodeling, and mucus accumulation. Importantly, the CF pigs were found to have a defect in their ability to eliminate bacteria from the airways, and this was evident within hours of birth and preceded any inflammatory reaction. Hence, infection may represent an initial step in the disease process that initiates the cascade of inflammation and pathology in CF lungs. The recently developed ferret model of CF manifests the multi-organ system involvement characteristics of human CF disease (including spontaneous development of diabetes) and provides another valuable model for dissecting early CF disease pathogenesis, determining how systemic disease in CF patients influences the progression of early lung disease, and developing novel prevention and therapeutic strategies.267
260 Ramsey BW, et al. N Engl J Med. 2011;365(18):1663–72. PMID: 22047557. Accurso FJ, et al. N Engl J Med. 2010;363(21):1991–2003. PMID: 21083385; Hutt DM, et al. Nat Chem Biol. 2010;6(1):25–33. PMID: 19966789; Okiyoneda T, et al. Science. 2010;329(5993):805–10. PMID: 20595578.
261 Accurso FJ, et al. N Engl J Med. 2010;363:1991–2003. PMID: 21083385; Ramsey BW et al. N Engl J Med. 2011;365(18):1633–72. PMID: 22047557.
262 Ramsey BW, et al. N Engl J Med. 2011;365(18):1633–72. PMID: 22047557.
263 Moran A, et al. Diabetes Care. 2009;32(10):1783–8. PMID: 19592632.
264 Wright FA, et al. Nat Genet. 2011;43(6):539–46. PMID: 21602797.
265 Nguyen D, et al. Science. 2011;334(6058):982–6. PMID: 22096200.
New information from the CF pig model indicates that loss of CFTR-dependent anion transport (chloride and bicarbonate) in newborn pigs is in itself sufficient for CF lung disease, as there was no evidence of excessive sodium reabsorption or airway surface liquid depletion in the airways of newborn pigs. Earlier studies suggested that increased sodium reabsorption and depletion of airway surface liquid may be key initiating events in CF lung disease. The CF pig model will be invaluable for investigating the connection between defective anion transport and immune defects, for evaluating early interventions to correct CFTR dysfunction and prevent progression, and for determining whether effects on infection and mucociliary clearance are primary or secondary.268
Priority research areas identified by NIH include:
In August 2011, NHLBI issued an initiative inviting grant applications to investigate the early origins of CF lung disease and the mechanisms involved in the development and progression of pulmonary abnormalities in infants and young children with this condition.269 In October 2011, NIDDK issued an initiative inviting grant applications to investigate the causes and consequences of CFRD. Review of these applications is underway.270
266 Gentzsch M, et al. J Biol Chem. 2010;285(42):32227–32. PMID: 20709758.
267 Stoltz DA, et al. Sci Transl Med. 2010;2(29):29ra31. PMID: 20427821. Sun X, et al. J Clin Invest. 2010;120(9):3149–60. PMID: 20739752.
268 Itani OA. Proc Natl Acad Sci U S A. 2011;108(25):10260–5. PMID: 21646513. Chen JH, et al. Cell. 2010;143(6):911–23. PMID: 21145458. Pier G, et al. Nat Med. 2011;17(2):166–7. PMID: 21297610.
269 For more information, see https://grants.nih.gov/grants/guide/rfa-files/RFA-HL-12-035.html.
270 For more information, see https://grants.nih.gov/grants/guide/rfa-files/RFA-DK-11-025.html.