Editing Stem Cells Could Lead to New Rheumatoid Arthritis Drug

Researchers with the Washington University School of Medicine in St. Louis, Shriners Hospitals for Children-St. Louis—along with investigators from Duke University and Cytex Therapeutics, Inc in Durham, North Carolina—have edited stem cells in mice to fight inflammation caused by arthritis and chronic conditions with a biologic drug.

The altered stem cells, known as SMART (Stem cells Modified for Autonomous Regenerative Therapy) cells, are capable of developing into cartilage cells that create a biologic anti-inflammatory drug. The drug can protect joints and tissue from damage caused by chronic inflammation.

Senior author and professor of orthopedic surgery at Washington University School of Medicine Farshid Guilak, PhD, said the research team’s goal is to package the rewired stem cells as an arthritis vaccine that delivers the anti-inflammatory drug “only when it is needed.”

“We want to use our gene-editing technology as a way to deliver targeted therapy in response to localized inflammation in a joint, as opposed to current drug therapies that can interfere with the inflammatory response through the entire body,” he said.

Many of the drugs currently used to treat arthritis are susceptible to interfering with the body’s immune system and causing side effects such as infections. This is because the drugs are given systematically and attack tumor necrosis factor-alpha (TNF-alpha), an inflammation-promoting molecule.

The SMART cells are capable of deciding when to attack inflammation, according to Guilak.

“If this strategy proves to be successful, the engineered cells only would block inflammation when inflammatory signals are released, such as during an arthritic flare in that joint,” he explained.

Using clustered, regularly interspaced short palindromic repeat (CRISPR) technology to replace a critical mediator of inflammation with a TNF-alpha inhibitor, the researchers grew responsive stem cells from mice samples.

In the following days, the team was able to direct the cells to grow into cartilage cells and produce inflammation-protected cartilage tissue. They also encoded the SMART cells with genes that would indicate when they were fighting inflammation by lighting up.

The successful implementation of rapid-activation therapy cells has the team seeking other uses. They are currently testing the stem cells in mouse models of rheumatoid arthritis and other inflammatory diseases, and are considering how it could aid systems that run on a feedback loop.

One such system is diabetic treatment. Guilak said it’s possible they could make stem cells that are capable of sensing glucose and activating insulin in response.

“We are using pluripotent stem cells, so we can make them into any cell type, and with CRISPR, we can remove or insert genes that have the potential to treat many types of disorders,” Guilak said.

Jonathan Brunger, PhD, the research’s first author and postdoctoral fellow in cellular and molecular pharmacology at the University of California, San Francisco, said the ability to building living tissues from these responding stem cells opens up “exciting possibilities for investigation in regenerative medicine.”

The research was detailed in a press release.

The research, “Genome Engineering of Stem Cells for Autonomously Regulated, Closed-Loop Delivery of Biologic Drugs,” is available in Stem Cell Reports journal.