Development of a Pegylated FN-Targeting Peptide as a Therapeutic and Diagnostic for Pulmonary Fibrosis
Abstract
Idiopathic pulmonary fibrosis (IPF) and other types of lung fibrosis are fatal diseases characterized by progressive scarring of the lungs. This group of diseases leads to the death of approximately 40,000 individuals in the U.S. each year. U.S. military Veterans are at increased risk for the development for IPF and other forms of lung fibrosis, as risk factors for IPF include age > 50, male sex, history of tobacco smoke use, and exposure to other agents that are associated with the development of pulmonary fibrosis (asbestos, burn pit smoke, dust storms). Other injuries to the lung (trauma or severe infection) can also lead to the development of lung scarring that can impair lung function and breathing. Unfortunately, treatments are limited. Existing treatments do not stop the progression of scarring of the lung (lung fibrosis) for the majority of patients with IPF. For these reasons, the goal of our research program is to identify new targets for therapy for IPF and other scarring lung diseases and develop these new therapies. Our group focuses on how the cells of the lung make scar (or fibrosis). We have found that these cells both make and assemble proteins, which comprise the developing scar. Specifically, specialized cells called myofibroblasts construct the early structure of the scar. This early scar structure is built using a protein called fibronectin. The fibronectin scaffold is crucial for building the remainder of the scar tissue. At the moment, there are no clinical therapies that can be used to disrupt the process of this early fibronectin scar formation. Our group has gathered strong initial data showing that we can disrupt fibronectin scar formation. Specifically, we have identified a small bacterial protein fragment (called FUD) that strongly binds to fibronectin, prohibiting it from forming into new scar. By using FUD, we can disrupt the overall fibrotic scar formation in the lab. To test the ability of FUD to treat lung fibrosis in a mouse model, we modified FUD to slow its clearance by the kidneys. Specifically, we increased its size by coupling it with polyethylene glycol (PEG) polymers, which is a technique used in other U.S. Food and Drug Administration (FDA)-approved medications for human diseases. We found that this modification of FUD (referred to as PEG-FUD) still allows it to readily bind to fibronectin and prevent formation of the fibronectin scar. PEG-FUD remains safe for administration to mice and increases the time circulating in the body, which improves its therapeutic potential. Importantly, we found that delivering PEG-FUD to mice with pulmonary fibrosis improved their survival and decreased the amount of lung fibrosis compared to mice who were treated with an inactive control molecule. In addition, by labeling PEG-FUD with a radioactive marker for positron emission tomography (PET) imaging, which is commonly used for cancer diagnosis and staging, we found that PEG-FUD targets lung fibrosis in mice. This means that PEG-FUD could potentially be used as a non-invasive method for visualizing lung fibrosis. With this in mind, we have assembled a team of researchers with a variety of relevant specialties (including a physician researcher with expertise in lung fibrosis, a professor of pharmacy with expertise in drug development and delivery, and a professor of radiology with expertise in development of imaging probes) in order to study the ability of PEG-FUD to treat fibrosis and serve as a non-invasive probe to assess lung fibrosis. In the first part of our grant (Aim 1), we will assess the ability of PEG-FUD to treat lung fibrosis (reduce scarring) in an experimental model of lung fibrosis in mice. We will find out how PEG-FUD affects the different phases of fibrosis in this model. In particular, we will determine the ability of PEG-FUD to reverse existing fibrosis, which would be important as we think about its potential to treat human lung fibrosis, because most patients
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210692
Entities
People
- Nathan Sandbo
Organizations
- United States Army
- University of Wisconsin–Madison