Targeted therapies developed to reduce lung fibrosis

WEST LAFAYETTE, Ind. – A new treatment option for lung fibrosis is being developed by Purdue University scientists. Lung fibrosis has been a concern for COVID-19 patients.

People with idiopathic pulmonary fibrosis (IPF) have a life expectancy of less than five years. Fibrotic diseases cause organ failure that lead to about 45% of all deaths in the United States. Existing therapies do little to slow progression.

Now, Philip S. Low, Purdue’s Ralph C. Corley Distinguished Professor of Chemistry and Presidential Scholar for Drug Discovery, has led a team to develop two targeted therapies for people with IPF. The two different therapeutic approaches are published in Science Translational Medicine and EMBO Molecular Medicine.

“This is a horrible disease that claimed the lives of my next-door neighbor and a good friend’s wife,” Low said. “We developed two targeted therapies that allow us to use powerful drugs with high toxicities because we specifically deliver them to diseased cells without harming healthy ones.”

The first of the Purdue team’s novel targeted molecules is designed to slow fibrosis and extend life. The second IPF therapy suppresses fibrosis-inducing cytokine production.

The two therapies will be moving into human clinical trials within the next several months. The developments come as a number of people with COVID-19 or who have recovered from COVID-19 experience lung fibrosis or other related conditions.

The therapy technologies are licensed through the Purdue Research Foundation Office of Technology Commercialization and optioned to MorphImmune, a startup co-founded by Low. For more information on licensing a Purdue innovation, contact the Office of Technology Commercialization at otcip@prf.org.

About Purdue Research Foundation

The Purdue Research Foundation is a private, nonprofit foundation created to advance the mission of Purdue University. Established in 1930, the foundation accepts gifts; administers trusts; funds scholarships and grants; acquires property; protects Purdue's intellectual property; and promotes entrepreneurial activities on behalf of Purdue. The foundation manages the Purdue Foundry, Purdue Office of Technology Commercialization, Purdue Research Park, Purdue Technology Centers and University Development Office. In 2020, the IPWatchdog Institute ranked Purdue third nationally in startup creation and in the top 20 for patents. The foundation received the 2019 Innovation and Economic Prosperity Universities Award for Place from the Association of Public and Land-grant Universities. For more information on licensing a Purdue innovation, contact the Purdue Office of Technology Commercialization at otcip@prf.org. For more information about involvement and investment opportunities in startups based on a Purdue innovation, contact the Purdue Foundry at foundry@prf.org.

About Purdue University

Purdue University is a top public research institution developing practical solutions to today’s toughest challenges. Ranked the No. 5 Most Innovative University in the United States by U.S. News & World Report, Purdue delivers world-changing research and out-of-this-world discovery. Committed to hands-on and online, real-world learning, Purdue offers a transformative education to all. Committed to affordability and accessibility, Purdue has frozen tuition and most fees at 2012-13 levels, enabling more students than ever to graduate debt-free. See how Purdue never stops in the persistent pursuit of the next giant leap at purdue.edu.

Writer: Chris Adam, cladam@prf.org 
Source: Philip Low, plow@purdue.edu

ABSTRACT

Targeted inhibition of PI3 kinase/mTOR specifically in fibrotic lung fibroblasts suppresses pulmonary fibrosis in experimental models

Suraj U. Hettiarachchi, Yen-Hsing Li, Jyoti Roy, Fenghua Zhang, Estela Puchulu-Campanella, Spencer D. Lindeman, Madduri Srinivasarao, Konstantin Tsoyi, Xiaoliang Liang, Ehab A. Ayaub, Cheryl Nickerson-Nutter, Ivan O. Rosas and Philip S. Low

Idiopathic pulmonary fibrosis (IPF) is a lethal disease with an average life expectancy of 3 to 5 years. IPF is characterized by progressive stiffening of the lung parenchyma due to excessive deposition of collagen, leading to gradual failure of gas exchange. Although two therapeutic agents have been approved from the FDA for IPF, they only slow disease progression with little impact on outcome. To develop a more effective therapy, we have exploited the fact that collagen-producing myofibroblasts express a membrane-spanning protein, fibroblast activation protein (FAP), that exhibits limited if any expression on other cell types. Because collagen-producing myofibroblasts are only found in fibrotic tissues, solid tumors, and healing wounds, FAP constitutes an excellent marker for targeted delivery of drugs to tissues undergoing pathologic fibrosis. We demonstrate here that a low–molecular weight FAP ligand can be used to deliver imaging and therapeutic agents selectively to FAP-expressing cells. Because induction of collagen synthesis is associated with phosphatidylinositol 3-kinase (PI3K) activation, we designed a FAP-targeted PI3K inhibitor that selectively targets FAP-expressing human IPF lung fibroblasts and potently inhibited collagen synthesis. Moreover, we showed that administration of the inhibitor in a mouse model of IPF inhibited PI3K activation in fibrotic lungs, suppressed production of hydroxyproline (major building block of collagen), reduced collagen deposition, and increased mouse survival. Collectively, these studies suggest that a FAP-targeted PI3K inhibitor might be promising for treating IPF.