
A team of scientists at Scripps Research and its drug discovery arm, the Calibr-Skaggs Institute for Innovative Medicines, has developed a druglike small molecule targeted to stimulate the growth of lung stem cells. The newly announced findings, published in the Proceedings of the National Academy of Sciences, offer a biological proof of concept for activating one of the body’s regenerative pathways and restoring damaged lung tissue. If successful, the novel treatment could transform outcomes for people who suffer from severe lung diseases, such as idiopathic pulmonary fibrosis (IPF).
“My approach toward regenerative medicine has been figuring out how to promote regenerative, proliferative repair of organs using druglike molecules that act on endogenous stem cell populations,” said co-senior author, Michael J. Bollong, PhD, an associate professor and the Early Career Endowed Roon Chair for Cardiovascular Research in the Department of Chemistry at Scripps Research. “We chose the lung because the stem cell population of the lower airway doesn’t regenerate as effectively as one ages.”
IPF is a progressive condition that affects up to 20 per 100,000 people worldwide, according to the National Library of Medicine. Currently, there are no available treatment options that repair lung tissue and reverse damage.
“Most drugs act by slowing the progression of disease—our approach is to make drugs that control cell fate to stop or reverse the disease process,” said Peter G. Schultz, PhD, co-senior author and president and CEO of Scripps Research.
The research team utilized ReFRAME, a drug repurposing library built by Calibr-Skaggs, to see whether existing drug mechanisms could increase growth of lung stem cells. ReFRAME permits researchers to rapidly sort through thousands of existing FDA-approved drugs and determine if they could treat any other major diseases. This approach is particularly useful for cellular systems that aren’t easily amenable to large-scale screening campaigns.
“ReFRAME allowed us to understand what the target was immediately, to start understanding how that biology made sense in the context of the lung, and to test the concept directly in vivo,” said Dr. Bollong.
Using ReFRAME, the Scripps Research and Calibr-Skaggs researchers determined that a drug class known as DPP4 inhibitors could potentially help activate production of lower airway stem cells, called type 2 alveolar epithelial cells (AEC2). Typically, DPP4 inhibitors are used as medications to control blood sugar for type 2 diabetes, but the team found that the inhibitors also promoted production of AEC2 in mice with damaged lungs. However, the dose required when using existing inhibitors for lung repair would be too high and unsafe for humans, therefore it wouldn’t be possible to directly repurpose approved inhibitors for clinical use, especially when used in combination with other antifibrotic drugs.
“To effectively repair the lungs, the dosing would be roughly 50 to 100 times as much, so we needed to make a drug that inhibited DPP4 in the lung only,” said Dr. Bollong. “That's why we went after a lung-targeted and lung-retained approach.”
Dr. Bollong and his team developed NZ-97, a DPP4 inhibitor that persists in the lungs and promotes AEC2 growth in mice with lung damage. While NZ-97 is a prototype drug, it’s chemically similar to CMR316, Calibr-Skagg’s drug that will be entering a phase 1 clinical trial in summer 2024. Dr. Bollong said that NZ-97 is a key component in demonstrating how CMR316 works from a pharmacological perspective.
Unlike preexisting DPP4 inhibitors, CMR316 will be administered once weekly via a nebulizer. The research team chemically modified these agents to be administered at very low doses and remain in the lungs for long periods, such that the drug selectively inhibits DPP4 only in this organ. The projected dose for humans is one to two mg over the span of a couple of minutes once per week.
“People have been making DPP4 inhibitors for more than 20 years, so we could leverage that known chemical matter to make a very good version of the drug that’s efficacious, lung retained and safe,” said Dr. Bollong.
The scientists are hopeful that CMR316 will also be able to assist with lung damage from a range of other pulmonary illnesses, including influenza, COPD and COVID-19.
“IPF makes the most sense as the first disease to investigate because it’s driven by a deficiency in this stem cell population,” said Dr. Bollong. “What we also show in this paper is that we've taken stem cells from IPF patient donors and replenish their capacity to grow at an ex vivo format.”