The goal of this proposal is to translate a type I collagen-specific positron emission tomography (PET) probe for human imaging and to assess its potential for direct imaging of pulmonary fibrosis in patients. Pulmonary fibrosis is a scarrin of the lungs that can arise from radiation injury, drug toxicity, environmental causes (e.g. silicosis) or from unknown cause, i.e. idiopathic pulmonary fibrosis (IPF). Despite the recent approval of two new drugs to treat IPF, it remains a deadly disease where average survival from time of diagnosis is only 2-3 years overall. Despite this rapid progression, the disease appears to be markedly heterogeneous both in its clinical course and pathogenesis. Current IPF imaging is carried out with high resolution computed tomography (HRCT) scanning, which may diagnose IPF non-invasively, however it cannot accurately predict prognosis or therapy response to any of the currently available treatments. Molecular imaging of fibrosis may be more sensitive than HRCT in detecting early fibrosis, and may also be able to distinguish new, active fibrosis from stable disease. A sensitive test that can identify early onset of fibrosis may have great utility i guiding interventions to alter the course of this devastating disease. The ability to stratify patients based on imaging active fibrosis could 1) guide patient therapy, 2) select patients for clinical trials, and 3) monitor for treatment response. The ability to see fibrosis regression prio to changes in functional tests would be an effective means to monitor the efficacy new therapeutic approaches. This proposal is in response to RFA-HL-16-001, Molecular Imaging of the Lung, Phase 2. In Phase 1 of this RFA we prepared a library of type 1 collagen targeted PET probes and screened them in the bleomycin mouse model of pulmonary fibrosis. We identified two similar probes that showed high specificity for pulmonary fibrosis and whose uptake in the lung correlated with increased collagen. We further showed that these probes could be used to monitor treatment response in a second mouse model of disease. Here, we will develop this technology for human use by performing preclinical studies to support an IND filing, and then evaluating the pharmacokinetics of the probe in healthy volunteers. To validate the probe, we will image lung cancer patients scheduled for lobectomy and correlate probe uptake with regions of lung histologically determined to be fibrotic. We will begin to implement this technology by imaging IPF patients and assessing whether increased probe uptake in IPF patients correlates with more progressive disease. The outcome of this 3-year research plan will be a collagen-specific PET probe that has been validated in patients with known pulmonary fibrosis. This research would enable further, larger trials to prospectively determine whether collagen-specific PET can stratify IPF patients, guide treatment planning, and/or monitor treatment response. The clinical course of IPF is very heterogeneous, and being able to accurately predict the prognoses of individual patients is a pressing need in both IPF patient care and research.

Public Health Relevance

Pulmonary fibrosis (scarring) is a devastating disease that results in difficulty breathing and ultimately death. This goal of this project is to take a positron emitting imaging probe that we have shown can detect fibrosis in animal models, and use it to detect fibrosis in human patients and predict their prognosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL131907-01
Application #
9090458
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Lin, Sara
Project Start
2016-04-15
Project End
2019-03-31
Budget Start
2016-04-15
Budget End
2017-03-31
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
Waghorn, Philip A; Jones, Chloe M; Rotile, Nicholas J et al. (2017) Molecular Magnetic Resonance Imaging of Lung Fibrogenesis with an Oxyamine-Based Probe. Angew Chem Int Ed Engl 56:9825-9828
Waghorn, Philip A; Oliveira, Bruno L; Jones, Chloe M et al. (2017) High sensitivity HPLC method for determination of the allysine concentration in tissue by use of a naphthol derivative. J Chromatogr B Analyt Technol Biomed Life Sci 1064:7-13
Désogère, Pauline; Tapias, Luis F; Hariri, Lida P et al. (2017) Type I collagen-targeted PET probe for pulmonary fibrosis detection and staging in preclinical models. Sci Transl Med 9: