The cells were developed at Washington University School of Medicine in St. Louis and Shriners Hospitals for Children-St. Louis, in collaboration with investigators at Duke University and Cytex Therapeutics Inc., both in Durham, North Carolina.
The researchers initially worked with skin cells taken from the tails of mice and converted those cells into stem cells. Then, using the gene-editing tool CRISPR in cells grown in culture, they removed a key gene in the inflammatory process and replaced it with a gene that releases a biologic drug that combats inflammation.
Their research has been published online by the journal
Stem Cell Reports.
“Our goal is to package the rewired stem cells as a vaccine for arthritis, which would deliver an anti-inflammatory drug to an arthritic joint but only when it is needed,” said Farshid Guilak, PhD, the paper’s senior author. “To do this, we needed to create a ‘smart’ cell.”
Many current drugs used to treat arthritis attack the inflammation-promoting molecule tumor necrosis factor-alpha (TNF-alpha). The problem with these drugs is that they are given systemically rather than targeted to joints. As a result, they interfere with the immune system throughout the body and can make patients susceptible to side effects such as infections.
“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,” Dr. Guilak said.
“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.”
As part of the study, Dr. Guilak and his colleagues grew mouse stem cells in a test tube and then used CRISPR technology to replace a critical mediator of inflammation with a TNF-alpha inhibitor.
“Exploiting tools from synthetic biology, we found we could re-code the program that stem cells use to orchestrate their response to inflammation,” said Jonathan Brunger, PhD, the paper’s first author.
Over the course of a few days, the team directed the modified stem cells to grow into cartilage cells and produce cartilage tissue. Further experiments by the team showed that the engineered cartilage was protected from inflammation.
“We hijacked an inflammatory pathway to create cells that produced a protective drug,” Dr. Brunger said.
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