The clinical techniques used to screen and evaluate new medications play a crucial role in determining how quickly safe and effective therapies can be made available to patients. We have developed an aerosol-based imaging technique for measuring liquid absorption in the airways that can be applied to screen new medications being developed to treat cystic fibrosis (CF). We propose to further develop this technique through a series of in vitro studies with airway cell cultures and in vivo studies involving child and adult CF patients. CF is an autosomal recessive disease that affects the lungs, pancreas, intestines, sinuses, skin, and liver. Airway liquid hyper-absorption causes the accumulation of dehydrated secretions and contributes significantly to the progression of CF lung disease. Modulation of airway liquid absorption is a common target of many therapeutic development efforts in CF. Our imaging technique involves the inhalation of two radiopharmaceuticals: one an absorbable small-molecule (In-DTPA) and the other a non-absorbable particle (Tc-SC). The total clearance of In-DTPA will include both mucociliary and absorptive components while Tc-SC is cleared only through the mucociliary route. The difference between the clearance rates of the radiopharmaceuticals therefore provides a measurement of DTPA absorption. Our preliminary in vitro data directly links DTPA absorption to liquid absorption and demonstrates therapeutic response. Our preliminary in vivo data demonstrate increased rates of In-DTPA absorption in the airways of CF patients. We hypothesize that DTPA absorption provides a quantifiable, non-invasive, measurement of airway liquid absorption that (a) is sensitive to CF genotype, (b) uniquely indentifies basic disease phenotype and predicts disease severity, and (c) is modulated by therapeutic interventions. All hypotheses are tested through both in vitro and in vivo studies. CF patients would benefit greatly from the development of new screening techniques to rank the many ongoing therapeutic development efforts. Most techniques currently available to evaluate new therapies track later-stage effects of the disease, and determining even preliminary efficacy can require lengthy studies and large numbers of patients. Our technique provides more rapid evaluation of therapeutic efficacy than any other technique currently available in the lung, and will speed the development of new therapies for CF.

Public Health Relevance

The clinical techniques used to screen and evaluate new medications play a crucial role in determining how quickly safe and effective therapies can be made available to patients. We have developed a new aerosol- based imaging technique for measuring liquid absorption in the airways that can be applied to screen new medications being developed to treat cystic fibrosis. Our technique provides more rapid evaluation of therapeutic efficacy than any other technique currently available in the lung, and will speed the development of new therapies for cystic fibrosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL108929-02
Application #
8302242
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Banks-Schlegel, Susan P
Project Start
2011-08-01
Project End
2016-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
2
Fiscal Year
2012
Total Cost
$378,750
Indirect Cost
$128,750
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Markovetz, Matthew R; Corcoran, Timothy E; Locke, Landon W et al. (2014) A physiologically-motivated compartment-based model of the effect of inhaled hypertonic saline on mucociliary clearance and liquid transport in cystic fibrosis. PLoS One 9:e111972
Locke, Landon W; Myerburg, Michael M; Markovetz, Matthew R et al. (2014) Quantitative imaging of airway liquid absorption in cystic fibrosis. Eur Respir J 44:675-84
Corcoran, Timothy E; Thomas, Kristina M; Brown, Stefanie et al. (2013) Liquid hyper-absorption as a cause of increased DTPA clearance in the cystic fibrosis airway. EJNMMI Res 3:14