By Pat Anson, Editor
A team of researchers has successfully used gene-editing technology to “rewire” mouse stem cells to fight inflammation – a finding that could pave the way for a new class of biologic drug that replaces cartilage and protect joints from damage caused by arthritis.
The stem cells, known as “smart” cells (stem cells modified for autonomous regenerative therapy), were developed at Washington University School of Medicine and Shriners Hospitals for Children in St. Louis, in collaboration with investigators at Duke University and Cytex Therapeutics in North Carolina.
The research findings are published in 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 senior author Farshid Guilak, PhD, a professor of orthopedic surgery at Washington University School of Medicine.
Guilak and his colleagues grew mouse stem cells in a test tube and then used a gene-editing tool called CRISPR to remove a gene that plays a key role in inflammation. That gene was replaced with a gene that releases a biologic drug that combats inflammation.
Within a few days, the modified stem cells grew into cartilage cells and produced cartilage tissue. Further experiments showed that the engineered cartilage was protected from inflammation.
"We hijacked an inflammatory pathway to create cells that produced a protective drug," explained Jonathan Brunger, PhD, the paper's first author and a postdoctoral fellow in cellular and molecular pharmacology at the University of California, San Francisco.
Many current biologic drugs used to treat arthritis – such as Enbrel, Humira and Remicade -- attack an inflammation-promoting molecule called TNF-alpha. But the problem with these drugs is that 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," said 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."
Researchers have begun testing the engineered stem cells in mouse models of rheumatoid arthritis and other inflammatory diseases. If the work can be replicated in living laboratory animals and then developed into a clinical therapy, the cartilage grown from stem cells would respond to inflammation by releasing a drug that protects them from further damage.
"When these cells see TNF-alpha, they rapidly activate a therapy that reduces inflammation," Guilak explained. "We believe this strategy also may work for other systems that depend on a feedback loop. In diabetes, for example, it's possible we could make stem cells that would sense glucose and turn on insulin in response.
"The ability to build living tissues from 'smart' stem cells that precisely respond to their environment opens up exciting possibilities for investigation in regenerative medicine."
Farshid Guilak and co-author Vincent Willard have a financial interest in Cytex Therapeutics, a startup founded by some of the investigators. They may license the technology and realize financial gain if it is eventually is approved for clinical use.
Guilak and his colleagues at Cytex have also used stem cells to grow new cartilage that could someday be implanted into arthritic hips, delaying or eliminating the need for hip replacement surgery.
Stem cells are found throughout the body and are increasingly being used to develop new treatments to repair damaged tissue and reduce inflammation. The Food and Drug Administration considers most stem cell treatments experimental because their safety and efficacy haven’t been proven through clinical studies.