Rewired cells automatically release biologic drug in response to inflammation in mouse study

The modified cells reduced inflammation and prevented a type of bone damage known as bone erosion in a mouse model of rheumatoid arthritis. The ultimate goal of the research team is to develop therapies for people with rheumatoid arthritis, a debilitating disease that affects approximately 1.3 million adults in the United States.

“Doctors often treat patients with rheumatoid arthritis with injections or infusions of anti-inflammatory biologic drugs, but these drugs can cause significant side effects when taken long enough and in doses high enough to work. beneficial, ”said lead researcher Farshid Guilak, PhD. , Professor Mildred B. Simon of Orthopedic Surgery. “We used CRISPR technology to reprogram genes in stem cells. Then we created a small cartilage implant by seeding the cells on woven scaffolds and placed them under the skin of mice. The approach allows these cells to stay in the body for a while. long and secrete medicine whenever there is a flare-up of inflammation. “

The new findings are published online September 1 in the journal Scientists progress.

The researchers used CRISPR-Cas9 genome editing technology to make cells that secrete a biological drug in response to inflammation. The drug reduces inflammation in the joints by binding to interleukin-1 (IL-1), a substance that often promotes inflammation in arthritis by activating inflammatory cells in a joint.

Guilak, co-director of the Washington University Center of Regenerative Medicine, and his team previously developed scaffolds that they cover with stem cells and then implant into joints to form cartilage. The strategy allows researchers to implant the modified cartilage cells so that they do not move away after a few days and can survive for months or longer.

His lab also previously built SMART cartilage cells (Stem Cells Modified for Autonomous Regenerative Therapy) using CRISPR-Cas9 technology to modify the genes in these cells so that when cartilage genes are turned on by inflammation, they secrete drugs in response.

In the new study, Guilak’s team combined strategies to provide treatment for rheumatoid arthritis.

“Cells stay under the skin or in a joint for months, and when they sense an inflammatory environment, they’re programmed to release a biologic drug,” said Guilak, also director of research at Shriners Hospitals for Children in St. Louis.

In this case, the drug was similar to the immunosuppressive drug anakinra, which binds to IL-1 and blocks its activity. Interestingly, this drug is not used frequently to treat rheumatoid arthritis because it has a short half-life and does not persist in the body for long. But in this study in mice, the drug reduced inflammation and prevented bone damage often seen in rheumatoid arthritis.

“We focused on bone erosion because it is a big problem for patients with rheumatoid arthritis, which is not treated effectively with current biologics,” said co-lead author Yunrak Choi, MD , guest orthopedic surgeon at the Guilak laboratory. “We used imaging techniques to closely examine the bones of the animals, and we found that this approach prevented bone erosion. We are very excited about this breakthrough, which appears to meet a significant clinical need. satisfied.”

Guilak collaborated with Christine Pham, MD, Director of the Rheumatology Division and Guy and Ella Mae Magness Professor of Medicine.

“Although biologics have revolutionized the treatment of inflammatory arthritis, continued administration of these drugs often results in adverse events, including an increased risk of infection,” Pham explained. “The idea of ​​providing such drugs primarily on demand in response to arthritis flares is extremely appealing to those of us working with arthritis patients, as the approach could limit the side effects that accompany it. continuous administration of high doses of these drugs. “

With CRISPR-Cas9 gene editing, cells have the potential to be programmed to make all kinds of drugs, meaning that if one arthritis drug works better than another in a particular patient, researchers could design cartilage cells to create personalized treatments. The strategy has great potential to treat other inflammatory arthritis conditions, including juvenile arthritis, a condition that affects more than 300,000 children in the United States.

“Many patients with arthritis have to self-administer these medications, injecting themselves daily, weekly or bi-weekly, while others go to a doctor every few months to receive an infusion of one. of these biologics, but in this study we have demonstrated that we can turn living tissue into a drug delivery system, ”said Kelsey H. Collins, PhD, postdoctoral research associate in the lab at Guilak et co. -first author of the study. “These cells can detect problems and respond by producing a drug. This approach also helps us understand why certain biologics may have limited effects in inflammatory arthritis. This is not because they do not bind to the correct target, but probably because an injected drug is short. -vive of the automatically controlled levels of drug released by implanted SMART cells. “

Researchers continue to experiment with CRISPR-Cas9 and stem cells, even engineered cells that could make more than one drug to respond to different triggers of inflammation.

This work was supported by Shriners Hospitals for Children and the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Institute on Aging, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Cancer Institute and the Office of the Director. from the National Institutes of Health (NIH). Grant numbers AG15768, AG46927, AR072999, AR076820, OD10707, OD021694, DK108742, AR073752, AR074992, AR067491, AR075899. P50 CA094056, P30 CA091842. Additional support from the Nancy Taylor Foundation for Chronic Diseases, the Arthritis Foundation, and the Washington University Center of Regenerative Medicine Phillip and Sima Needleman Fellowship.