A drug prototype regenerating lung tissue

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For many progressive lung diseases like idiopathic pulmonary fibrosis (IPF), a key issue is a low supply of new stem cells to repair and reverse damage.
But a team of scientists at Scripps Research and its drug discovery arm, the Calibr-Skaggs Institute for Innovative Medicines, has now developed a lung-targeted, druglike small molecule to stimulate the growth of lung stem cells.
“We chose the lung because the stem cell population of the lower airway doesn’t regenerate as effectively as one ages.”
To see whether existing drug mechanisms could increase growth of lung stem cells, the team turned to ReFRAME, a drug repurposing library built by Calibr-Skaggs.
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 a few months.
Unlike preexisting DPP4 inhibitors, CMR316 will be administered once weekly via a nebulizer—a machine that generates a medicinal mist to inhale—so it’s delivered directly to the lungs.
The research team also chemically modified these agents to remain in the lungs for long periods, such that the drug selectively inhibits DPP4 only in this organ.
“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.”


Globally, pulmonary disorders are the primary cause of morbidity and mortality. Lack of new stem cells to reverse and repair damage is a major problem for many progressive lung diseases, such as idiopathic pulmonary fibrosis (IPF). Lung function declines and a host of serious illnesses can develop in the absence of these cells, which are in charge of promoting the growth and regeneration of healthy tissue.

However, a group of researchers at Scripps Research and its drug development division, the Calibr-Skaggs Institute for Innovative Medicines, have created a drug-like small molecule that targets the lung and promotes the growth of lung stem cells. These novel discoveries offer a biological proof of concept for triggering the body’s regenerative pathways and healing damaged lung tissue. They were published in the Proceedings of the National Academy of Sciences.

This strategy may change the way severe pulmonary diseases are treated, especially since a phase 1 clinical trial for CMR316, a medication that is similar to what Calibr-Skaggs is developing to treat IPF, is about to begin this summer.

“My approach to regenerative medicine has been to find druglike molecules that act on endogenous stem cell populations to promote regenerative, proliferative repair of organs,” says co-senior author Michael J. Bollong, Dr. B. is an associate professor at Scripps Research and the Early Career Endowment Roon Chair for Cardiovascular Research in the Department of Chemistry. We selected the lung because as people age, the lower airway’s stem cell population doesn’t regenerate as well. “.

This indicates increased secretion of scar tissue, which may result in IPF, an illness that affects up to 20 persons out of every 100,000 worldwide, according to the National Library of Medicine. Unfortunately, there aren’t any treatments on the market right now that can repair damaged lung tissue.

In order to halt or reverse the disease process, Peter G. says, “our approach is to make drugs that control cell fate.” Most medications work by slowing the progression of the illness. Schultz, Ph. D. co-senior author as well as Scripps Research’s president and CEO.

The group looked to ReFRAME, a drug repurposing library developed by Calibr-Skaggs, to determine whether current drug mechanisms could promote the growth of lung stem cells. With ReFRAME, scientists can quickly sift through thousands of FDA-approved medications to see if any of them could be used to treat additional serious illnesses. This method works especially well for cellular systems that are difficult to target with extensive screening efforts.

“We were able to test the concept in vivo and quickly determine what the target was thanks to ReFRAME,” says Bollong. “We also started to understand how that biology made sense in the context of the lung.”.

The team, which also consists of researchers Sida Shao, Nan Zhang, Sean B., and others from Calibr-Skaggs and Scripps Research, used ReFRAME. Joseph, Arnab K. Researchers Chatterjee and Jeffrey Jian Chen discovered that a class of medications called DPP4 inhibitors may be able to stimulate the production of type 2 alveolar epithelial cells (AEC2), which are stem cells found in the lower airways.

The researchers discovered that DPP4 inhibitors increased the production of AEC2 in mice with damaged lungs, despite the fact that the drugs are frequently used to control blood sugar in type 2 diabetes. Approved inhibitors cannot, however, be directly repurposed for clinical use because the dose needed to use them for lung repair would be too high and dangerous for humans, especially when combined with other anti-fibrotic medications.

Bollong explains, “We needed to make a drug that inhibited DPP4 in the lung only, because the dose required to repair the lungs would be roughly 50 to 100 times as much.”. For this reason, we pursued a lung-targeted and lung-retained strategy. “.

NZ-97, a DPP4 inhibitor that sticks in the lungs and encourages AEC2 growth in mice with lung damage, was created by Bollong and his colleagues. Although NZ-97 is a prototype, it shares chemical similarities with Calibr-Skagg’s drug CMR316, which is about to start a phase 1 clinical trial.

In contrast to current DPP4 inhibitors, CMR316 will be given once a week by means of a nebulizer, a device that produces a medicating mist for inhalation, thereby delivering the medication straight to the lungs. The scientists also chemically altered these substances to enable them to stay in the lungs for extended periods of time, selectively inhibiting DPP4 in the lungs alone.

In the end, Bollong says, “that allowed us to have a drug that could be administered at very low doses.”. In actuality, the recommended dosage for humans is one weekly inhalation of 1 to 2 milligrams spread over a few minutes. Given that DPP4 inhibitors have been produced for more than 20 years, we could use this established chemical knowledge to create a highly effective, safe, and lung-retained version of the medication. “.”.

With influenza, COVID-19, and chronic obstructive pulmonary disease (COPD), the third greatest cause of death worldwide, among other pulmonary illnesses, Bollong, Schultz, and the rest of the research team hope that CMR316 will also help with lung damage.

“Because IPF is caused by a deficiency in this stem cell population, it makes the most sense to look into it first,” Bollong says, noting that NZ-97 demonstrated generalizable efficacy in a variety of lung damage models. The study also demonstrates how we have restored the donors’ stem cells’ ability to proliferate ex vivo using stem cells from IPF patients. Thus, NZ-97 plays a crucial role in demonstrating the pharmacological mechanism of action of CMR316.

Along with developing compounds with novel mechanisms to aid in heart cell regeneration and repair from heart failure—along with employing small molecule drugs to replenish organs like the cornea, kidney, and colon—the research team is also working toward the goal of having CMR316 available for use in the clinic in the near future.

The study’s other authors are Sida Shao, Nan Zhang, Gregory P., and Bollong in addition to Schultz. Specht, Shaochen You, Lirui Song, Qiangwei Fu, David Huang, Hengyao You, Alain Domissy, Shuangwei Li, Van Nguyen-Tran, Sean B. Joseph, Kinnab K. Jian Shu of Harvard University; Chatterjee and Jeffrey Jian Chen of Scripps Research.

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