Combining two cellular-editing processes, researchers have developed cartilage that fights inflammation. The scientists hope that the breakthrough could eventually lead to localized injections that combat arthritis or perhaps a vaccine that would eliminate the condition altogether.
Like many of the biology breakthroughs happening today, the WU researchers started with stem cells. To be more accurate, they actually started with skin cells from the tails of mice and converted them into stem cells. They then used a gene-editing technique called CRISPR to remove a gene involved in inflammation and replace it with one that releases an anti-inflammatory drug. The resulting cells are known as SMART cells, which stands for Stem cells Modified for Autonomous Regenerative Therapy.
"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, the senior author of a paper about the work and a professor of orthopedic surgery at Washington University School of Medicine. "To do this, we needed to create a 'smart' cell."
As part of the current fight against arthritis, there are several drugs that work to eliminate an inflammatory molecule called tumor necrosis factor-alpha (TNF-alpha). The issue with such drugs, however, is that they work throughout the entire body, rather than only at the site of inflammation, and can have an impact on the body's overall immune system.
To change this dynamic, the researchers replaced the gene that expresses TNF-alpha with one that inhibits it by releasing a drug, basically converting the cells from those that create inflammation to those that fight it. "We hijacked an inflammatory pathway to create cells that produced a protective drug," said Jonathan Brunger, a postdoctoral fellow in cellular and molecular pharmacology at the University of California, San Francisco. They then coaxed these cells to grow into cartilage in the lab which, they found, was successful in combating inflammation.
The hope is that injecting the cells into areas afflicted by arthritis, the new anti-inflammatory cartilage could replace the old cartilage. This would effectively create a vaccine against the condition, as the newly engineered cells would only release the anti-inflammatory drug when inflammation is present – such as during an arthritic flare-up – and turn off the release of the drug when the flare subsides.
Additionally, the researchers also engineered the new cells to light up when they responded to inflammation so that they could track their response in the body. The cells are now being tested in mice with rheumatoid arthritis and other inflammatory disorders and the researchers think that the method of combining stem cells with CRISPR could help fight other diseases as well.
"We believe this strategy also may work for other systems that depend on a feedback loop," said Guilak. "In diabetes, for example, it's possible we could make stem cells that would sense glucose and turn on 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."
The paper is published in the journal Stem Cell Reports.
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