Scripps Research and Calibr-Skaggs scientists are tapping into the body’s regenerative pathways to repair damaged organs — potentially undoing the wear-and-tear that comes with aging.

The world’s population is predicted to reach 2.1 billion people aged 60 years or older by 2050, according to the World Health Organization’s most recent projections. As humans age, the body’s ability to repair and replace tissue declines, resulting in illness and infirmity. This begs the question: How can science and medicine help people around the globe stay healthy as they live longer?

To address this pressing need, Calibr-Skaggs and Scripps Research scientists have developed a unique approach to coaxing a patient’s own stem cells into regenerating new, healthy tissue. They’re pursuing a strategy of developing small molecule drugs that work to control the fate of endogenous stem cells—those found within tissues—to repair tissue damage. These first-in-class regenerative medicines could globally address a range of chronic and aging-associated illnesses, like osteoarthritis, heart disease, macular degeneration, inflammatory bowel disease and much more.

At the center of this strategy is Michael Bollong, associate professor of chemistry and the Early Career Endowed Roon Chair for Cardiovascular Research. Bollong is using a variety of drug screening techniques and target identification experiments to halt—with the potential to even reverse—these severe diseases that tend to manifest as we grow older.

“As we start to develop drugs that promote lifespan, these treatments could be paradigm-shifting in the way we think about aging,” Bollong says. “It’s ultimately something I think can only be done at Scripps Research, with our institute’s translational medicine focus. There’s a dedication of real resources not only to basic science but also to drug development and the creation of new medicines. That’s why I’m here.”

Breathing easier

One of these therapies is an inhaled drug prototype called CMR316. This small molecule is designed to restore damaged lung tissue in cases of idiopathic pulmonary fibrosis (IPF), a severe and deadly disease that typically occurs in people older than 50 years. CMR316, which is delivered directly to the lungs via an inhalable medicinal mist, has been proven to stimulate the growth of lung stem cells in numerous preclinical models. The therapy, funded in part by the Bachrach Family Foundation, recently entered a phase 1 clinical trial in Europe.

If CMR316 successfully combats IPF, scientists are optimistic that it can also restore tissue damaged from other lung pathologies, including those caused by respiratory infections.

“This could be used for multiple indications, including silicosis and chronic obstructive pulmonary disease,” notes Sean Joseph, vice president of nonclinical development at Calibr-Skaggs. “It may even be effective for pollution-related illnesses, which would help regions where smoke pollution is a major issue.”

Using ReFRAME—Calibr-Skaggs’ extensive drug repurposing library—Bollong and team determined that a drug class known as DPP4 inhibitors could likely activate production of stem cells in the lower airway. DPP4 inhibitors are approved medications to control blood sugar in cases of type 2 diabetes. But there was a problem: The dose required for lung tissue regeneration would be too high and unsafe for humans, meaning the inhibitors couldn’t be directly repurposed.

“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 lungs only,” explains Bollong. “That’s why we went after a lung-targeted and lung-retained approach.”

The research team expects that CMR316 will work in conjunction with treatments that already exist for many pulmonary illnesses.

“There are several drugs that can stop fibrosis and inflammation, but ours is actually regenerating lung tissue,” adds Joseph.

Leaving no tissue unturned

The team’s regenerative medicine pipeline extends well beyond the lung, spanning countless other organs and tissue types. This includes targeting the regenerative factor in humans called yes-associated protein (YAP), which controls organ size and tissue regeneration.

In the lab, Bollong wondered whether activating YAP when it should be “turned off” would regenerate heart muscle cells. With the help of ReFRAME again, Bollong’s team found several drug-like small molecules that “turn on” YAP. And in preclinical models, activating YAP promoted regenerative cardiac repair and reversed heart failure. A phase 1 clinical trial is anticipated over the next couple of years, with the team now developing a one-time injectable to deliver via the sac that surrounds the heart. The hope is that such a medicine could undo the extensive muscular damage caused by heart attacks.

The regenerative medicine pipeline also includes small molecules that expand the retinal pigmented epithelial layer depleted in macular degeneration, replenish the damaged intestinal barrier in inflammatory bowel disease, and promote cartilage growth—the last of which, KA34, is currently in clinical testing.

While other types of stem cell therapies show considerable potential, their benefits have yet to be fully realized, and they would be costly and complex to administer. Scripps Research and Calibr-Skaggs’ approach is an elegant solution that would be more affordable than other stem cell treatments.

“My ultimate goal is to be able to develop a regenerative medicine for every one of our internal organs, like the heart or the lungs. But what about the kidney? What about the retina?” Bollong asks. “There’s many other areas we can work on, and I’m excited to hopefully bring those forward to the clinic.”