Using new gene-editing technology, researchers have rewired computer mouse stem cells to fight inflammation caused by arthritis along with other chronic conditions. Such stem cells, known as SMART tissues (Stem cells Modified for Autonomous Regenerative Therapy), grow into cartilage cells that produce a biologic anti-inflammatory drug that will, ideally, will replace arthritic cartilage and simultaneously secure joints and other tissues from damage that occurs with persistent inflammation.
The cells were created at Washington University School of Medicine in St Louis and Shriners Hospitals for Children-St. Louis, within collaboration with investigators at Duke University and Cytex Therapeutics Inc., both in Durham, N. C. The experts initially worked with skin cells taken from the tails associated with mice and converted those cells into stem cellular material. Then, using the gene-editing tool CRISPR in cells developed in culture, they removed a key gene in the inflamed process and replaced it with a gene that produces a biologic drug that combats inflammation.
The research is available online April 27 in the journal Stem Cell Reports .
“Our goal is to package the rewired stem cells being a vaccine for arthritis, which would deliver an anti-inflammatory medication to an arthritic joint but only when it is needed, inch said Farshid Guilak, PhD, the paper’s senior writer and a professor of orthopedic surgery at Washington College School of Medicine. “To do this, we needed to produce a ‘smart’ cell. ”
Many current medicines used to treat arthritis — including Enbrel, Humira plus Remicade — attack an inflammation-promoting molecule called growth necrosis factor-alpha (TNF-alpha). But the problem with these drugs is they are given systemically rather than targeted to joints. As a result, they hinder the immune system throughout the body and can make patients susceptible to unwanted effects such as infections.
“We want to use our own gene-editing technology as a way to deliver targeted therapy in response to local inflammation in a joint, as opposed to current drug therapies that may interfere with the inflammatory response through the entire body, ” mentioned Guilak, also a professor of developmental biology and of biomedical engineering and co-director of Washington University’s Center associated with Regenerative Medicine. “If this strategy proves to be successful, the designed cells only would block inflammation when inflammatory indicators are released, such as during an arthritic flare for the reason that joint. ”
As part of the study, Guilak great colleagues grew mouse stem cells in a test pipe and then used CRISPR technology to replace a critical mediator associated with inflammation with a TNF-alpha inhibitor.
“Exploiting equipment from synthetic biology, we found we could re-code this program that stem cells use to orchestrate their response to irritation, ” said Jonathan Brunger, PhD, the paper’s initial author and a postdoctoral fellow in cellular and molecular pharmacology at the University of California, San Francisco.
Over the course of a few days, the team directed the modified originate cells to grow into cartilage cells and produce the fibrous connective tissue cartilage tissue. Further experiments by the team showed that the manufactured cartilage was protected from inflammation.
“We hijacked an inflammatory pathway to create cells that created a protective drug, ” Brunger said.
The researchers also encoded the stem/cartilage cells along with genes that made the cells light up when responding to irritation, so the scientists easily could determine when the cells had been responding. Recently, Guilak’s team has begun testing the designed stem cells in mouse models of rheumatoid arthritis and other inflamed diseases.
If the work can be replicated within animals and then developed into a clinical therapy, the manufactured cells or cartilage grown from stem cells might respond to inflammation by releasing a biologic drug — the TNF-alpha inhibitor — that would protect the artificial cartilage cells that Guilak’s team created and the organic cartilage cells in specific joints.
“When these cells see TNF-alpha, they rapidly activate the therapy that reduces inflammation, ” Guilak explained. “We believe this strategy also may work for other systems that depend on the feedback loop. In diabetes, for example , it’s possible we could create stem cells that would sense glucose and turn on insulin in response. We are using pluripotent stem cells, so we could make them into any cell type, and with CRISPR, we are able to remove or insert genes that have the potential to treat a number of disorders. ”
With an eye toward additional applications of this approach, Brunger added, “The ability to develop living tissues from ‘smart’ stem cells that specifically respond to their environment opens up exciting possibilities for analysis in regenerative medicine. ”