Researchers at Washington University School of Medicine in St. Louis have genetically engineered cells that, when implanted in mice, deliver a biologic drug in response to inflammation.
These cells reduced inflammation and prevented bone erosion in a mouse model of rheumatoid arthritis. The research team aims to develop therapies for this condition, which affects about 1.3 million adults in the United States.
“Doctors often treat patients who have rheumatoid arthritis with injections or infusions of anti-inflammatory biologic drugs, but those drugs can cause significant side effects when delivered long enough and at high enough doses to have beneficial effects,” said senior investigator Farshid Guilak, the Mildred B. Simon Professor of Orthopedic Surgery.
“We used CRISPR technology [CRISPR-Cas9] to reprogram the genes in stem cells. Then we created a small cartilage implant by seeding the cells on woven scaffolds, and we placed them under the skin of mice. The approach allows those cells to remain in the body for a long time and secrete a drug whenever there is a flare of inflammation,” he added. The findings were published online in Science Advances.
Guilak, a co-director of the Washington University Center of Regenerative Medicine, and his team previously developed scaffolding that they coat with stem cells and then implant into joints to form cartilage. The strategy allows the researchers to implant the engineered cartilage cells in such a way that they don’t drift away after a few days and can survive for months or longer. “The cells sit under the skin or in a joint for months, and when they sense an inflammatory environment, they are programmed to release a biologic drug,” said Guilak.
In this study, the drug used was similar to the immunosuppressant drug anakinra, which binds to IL-1 and blocks its activity. That drug isn’t used frequently to treat rheumatoid arthritis because it has a short half-life and doesn’t linger 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 that is a big problem for patients with rheumatoid arthritis, which is not effectively treated by current biologics” said co-first author Yunrak Choi, a visiting orthopedic surgeon in the Guilak lab. “We used imaging techniques to closely examine bones in the animals, and we found that this approach prevented bone erosion. We’re very excited about this advance, which seems to meet an important unmet clinical need.”
Guilak also collaborated with Christine Pham, director of the Division of Rheumatology and the Guy and Ella Mae Magness Professor of Medicine.
“Although biologics have revolutionized the treatment of inflammatory arthritis, the continuous administration of these drugs often leads to adverse events, including an increased risk of infection,” Pham explained.
“The idea of delivering such drugs essentially on demand in response to arthritis flares is extremely attractive to those of us who work with arthritis patients, because the approach could limit the adverse effects that accompany continuous high-dose administration of these drugs.”
With CRISPR-Cas9 gene editing, cells have the potential to be programmed to make all sorts of drugs, meaning that if one arthritis drug works better than another in a particular patient, the researchers could engineer cartilage cells to make 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.
