The goal of this proposal is to develop a type I collagen-specific positron emission tomography (PET) probe for direct imaging of pulmonary fibrosis. Pulmonary fibrosis is a disease marked by scarring (fibrosis) in the lungs. As the lung tissue becomes scarred, it interferes with a person's ability to breathe. In some cases, the cause of fibrosis can be found, but the majority of cases are termed idiopathic pulmonary fibrosis (IPF), i.e. there is no known cause. IPF affects an estimated 90,000 people in the United States and >5 million patients worldwide. There is no effective treatment and many people with the disease live only about three to five years after diagnosis. While recent clinical trials have been disappointing, there are promising therapies at the preclinical stage. IPF is a disease area that would benefit greatly from a molecular imaging approach. IPF patients are identified at a late stage of disease where prognosis is poor. A sensitive test that can identify early onset of fibrosi may have great utility in guiding interventions to alter the course of this devastating disease. The development of new therapeutic approaches would also benefit from a noninvasive, sensitive measure of fibrosis. The ability to see fibrosis regression prior to changes in functiona tests would be an effective means to monitor the efficacy new therapeutic approaches and could be a means of testing efficacy in smaller numbers of subjects before embarking on large, expensive clinical trials. This proposal is in response to RFA-HL-12-036, """"""""Molecular Imaging of the Lung"""""""". In particular it responds to the specific need for """"""""Probes of fibrotic activity and scarring"""""""". To address the translational imperative of the RFA that """"""""probes be feasible for use in human subjects"""""""", we propose the development of a novel PET probe. The regulatory path to an investigational new drug (IND) application is clear and PET probes can take advantage of the exploratory IND mechanism that results in rapid proof of concept in human subjects. Our approach is to take a known peptide that has affinity and specificity for type I collagen. Overproduction of type I collagen is a hallmark of fibrosis. We have previously used this peptide conjugated to gadolinium for MR imaging of cardiac and liver fibrosis. Here we will modify the peptide to incorporate a positron emitter to take advantage of the high sensitivity of PET in order to quantify fibrosis in the lung. Preliminary data shows the feasibility of this approach to image fibrosis. This proposal aims to optimize a collagen-specific PET probe for ultimate human use.
In Aim 1 we build compound libraries and label probes with fluorine-18 positron emitters to identify probes with optimal collagen affinity, specificity, and metabolic stability.
In Aim 2, we examine the efficacy of collagen-specific probes in identifying and quantifying fibrosis in mouse models.
In Aim 3 we demonstrate the utility of an optimized collagen-specific PET probe in a pig model of pulmonary fibrosis. The output of this research will be a novel fibrosis imaging probe with demonstrated efficacy, pharmacokinetic characterization, and preclinical dosimetry data that enables rapid translation for human use.
Pulmonary fibrosis (scarring) is a devastating disease that results in difficulty breathing and ultimately death. This goal of this project is to identify a positron emitting imaging probe and imaging methodology to noninvasively and directly detect fibrosis, and to provide a tool to monitor whether new therapies for pulmonary fibrosis are effective. (End of Abstract)
|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|
|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|
|Shea, Barry S; Probst, Clemens K; Brazee, Patricia L et al. (2017) Uncoupling of the profibrotic and hemostatic effects of thrombin in lung fibrosis. JCI Insight 2:|
|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:|
|Caravan, Peter; Yang, Yan; Zachariah, Roshini et al. (2013) Molecular magnetic resonance imaging of pulmonary fibrosis in mice. Am J Respir Cell Mol Biol 49:1120-6|