Optimization and development of extracellular matrix-targeting probes for PET-based assessment of lung fibrosis disease activity

Idiopathic pulmonary fibrosis (IPF) is a rapidly progressing disease characterized by relentless extracellular matrix (ECM) deposition and lung stiffening that leads to death 3-4-years after diagnosis. IPF disease monitoring largely relies on high-resolution computed tomography imaging and pulmonary function tests, which are unable

to assess ECM deposition or real-time disease activity. Since there is currently no method to evaluate ECM deposition and real-time disease activity, and given the importance of determining disease progression in therapeutic decision-making, there is a critical need for improved methods to assess IPF disease activity in real-

time. Dr. Bernau's long-term goal is to establish an independent research career dedicated to developing new molecular imaging methods that facilitate diagnosis and treatment of disorders characterized by aberrant wound healing, especially IPF. Molecular probes optimized for positron emission tomography (PET) imaging enable

sensitive assessment of target engagement, making this an attractive modality for non-invasive monitoring of disease activity. In this proposal, Dr. Bernau will leverage her expertise in matrix biology of IPF, small animal imaging with training in PET imaging, probe development, pharmacology, and additional animal models of lung

fibrosis to develop a novel PET probe optimized to determine the activity and treatment response of human IPF. Fibronectin (FN) is an abundant glycoprotein that is highly upregulated during IPF, serves as a scaffold for other ECM proteins, including collagens, and is localized to fibroblastic foci, the leading edge of active fibrosis.

Due to its essential role in early phases of the fibrotic process, the rationale for this proposal is that identifying regions of nascent FN deposition can serve as a tool for distinguishing active fibrosis and assessing disease progression. Dr. Bernau and her team developed a novel probe (PEG-FUD) that is innovative in its capacity to

target early ECM deposition in fibroblastic foci in human IPF and early pro-fibrotic phases of bleomycin-induced pulmonary fibrosis in mice (via in vivo PET imaging). The objective of this proposal is to address the probe's key characteristics for detection of fibrotic disease activity and adapt it for downstream clinical translation, including

optimization of its signal to background ratio within 1 h post-injection. To accomplish this, Dr. Bernau Aims to: 1) Optimize FUD's imaging performance while preserving FN binding affinity in vitro and in vivo, and 2) Determine how 64Cu-PEG-FUD probe can monitor disease progression and response to antifibrotic therapies. Dr. Bernau

is supported by the rich research infrastructure and resources of her Mentorship and Advisory Committee, the Department of Medicine, and the University of Wisconsin-Madison. These studies will enable Dr. Bernau's future work focused on subsequent pre-clinical developments of PEG-FUD as a probe for active lung fibrosis.

Importantly, this project and training period will serve as a foundation for an independent research career focused on molecular probe development for IPF and other disorders characterized by aberrant wound healing, informing the choice of optimal treatment and improving morbidity and mortality for these devastating conditions.