Anyone who’s had a knee or other joint replacement surgery knows what an ordeal the procedure can be. But for many sufferers of osteoarthritis, the most common form of arthritis, damage to the joints’ cartilage leaves them with few other options. Most medications for the condition focus on pain relief and don’t slow the progression of the disease.
An emerging class of therapies known as senolytics holds the promise to treat cells that contribute to arthritis, potentially delaying or even bypassing the need for invasive surgeries. Dormant cells, also known as senescent cells, can accelerate or trigger osteoarthritis. Senolytic therapies, some of which have been approved by the Food and Drug Administration for cancer and other conditions, target senescent cells and are being tested in clinical trials for arthritis. But there’s been a holdup: Scientists have had no way to visualize the therapies’ cellular target in the body.
Now, a team of researchers from Stanford Medicine and Northwestern University have developed an MRI contrast agent that lights up these dormant cells. The non-invasive imaging method could be used to identify patients eligible for senolytic therapies and track the treatments’ progress in the body. A paper describing their technique was published May 3 in the journal npj Imaging.
“As we age, we accumulate senescent cells. These are like ‘zombie cells’ — they’re not dead, they’re alive, but they’re not growing and dividing like other cells,” said Vidyani Suryadevara, PhD, an instructor in radiology at Stanford Medicine who is one of the lead authors on the study. “There are several new senolytic therapies that are in the works, but for us to monitor how effective and efficient those treatments are, we need imaging tools.”
Previous animal studies have shown that senolytic drugs can reverse osteoarthritis by eliminating these age-related senescent cells, giving the body a chance to repair and rejuvenate the missing cartilage that is a hallmark of osteoarthritis.
Caged contrast
The newly developed contrast agent is a riff on a commonly used MRI agent, gadolinium, with an added chemical “cage” around the gadolinium that opens only when the agent encounters a protein called beta-galactosidase that is present at high levels in senescent cells. In its standard use, gadolinium lights up all tissues in the body; the scientists showed that their caged contrast agent lights up only senescent cells. They say it could be injected intravenously or directly into arthritic joints.
In their study, the researchers tested the caged contrast in live pigs and in pig knee joint specimens. They implanted human senescent and non-senescent cells into specific places in the joint; the agent lit up only the group of senescent cells. Further studies to prove this concept in human knee specimens (removed during knee replacement surgery) are underway.
Currently, there’s no way to determine whether the senolytic therapy eliminates senescent cells. We envision that our contrast agent could fill this gap.”
The idea for the project came about when two of the senior authors on the study, Heike Daldrup-Link, MD, a Stanford Medicine professor of radiology, and Thomas Meade, PhD, a professor of chemistry at Northwestern University, got to talking at a conference a few years ago. Meade and his team at Northwestern had developed the beta-galactosidase-specific contrast agent as a non-invasive way to track dosages of gene therapies for other conditions. Daldrup-Link was looking for a way to visualize senescent cells and realized the agent Meade had developed might do the trick.
“MRI has this great advantage of being non-invasive, and the technology is everywhere. It’s not like you have to invent a new instrument,” Meade said. He has founded a startup company, PreDx, to further develop this and related imaging tools.
The researchers hope their agent can identify patients who might benefit most from senolytic therapies — those with the highest levels of dormant cells — and help speed clinical trials by showing whether the treatments reduce the number of senescent cells in the body. Current clinical trials focused on these therapies measure patient outcome, or whether a person’s symptoms of arthritis are improving, and often need to follow patients for months or years to show meaningful measurements. Their imaging method could provide answers within weeks, Daldrup-Link said.
“Currently, there’s no way to determine whether the senolytic therapy eliminates senescent cells,” she said. “We envision that our contrast agent could fill this gap.”
Senescent cells in other contexts
The agent could also be used to detect and measure senescent cells in other diseases, the researchers said. Aging increases senescent cells in the body, and these cells have been implicated in a wide range of diseases and disorders, from cancer to Alzheimer’s disease to metabolic disorders.
“Many of these processes, in one way or another, circle back to senescence and aging,” said Kerem Nernekli, MD, a former postdoctoral research fellow at Stanford Medicine and entering radiology resident at Mount Sinai West in New York who is one of the lead authors on the study.
The study was funded by the National Institutes of Health (grant UG3CA268112). The development of the probe and core facilities supporting this research were funded through the National Institutes of Health (grants R01AR054458, 5R01NS115571, 5R01EB005866-08, P30CA060553 and P30CA124435) and the NASA Ames Research Center (grant NNA06CB93G).
