Is This the First Step Toward a Vaccine Targeting Inflammation in the Joints?
Using new gene-editing technology, researchers have rewired mouse stem cells to fight inflammation caused by arthritis and other chronic conditions.
These SMART cells (Stem cells Modified for Autonomous Regenerative Therapy) develop into cartilage cells that produce a biologic anti-inflammatory drug which, ideally, will replace arthritic cartilage and simultaneously protect joints and other tissues from damage that occurs with chronic inflammation.
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 — including Enbrel, Humira and Remicade — 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.
The researchers also encoded the stem/cartilage cells with genes that made the cells light up when responding to inflammation, which allowed them to easily determine when the cells were responding. Recently, Dr. Guilak’s team has begun testing the engineered stem cells in mouse models of rheumatoid arthritis and other inflammatory diseases.
If the work can be replicated in animals and then developed into a clinical therapy, the engineered cells or cartilage grown from stem cells would respond to inflammation by releasing a biologic drug — the TNF-alpha inhibitor — that would protect the synthetic cartilage cells that Dr. Guilak’s team created and the natural cartilage cells in specific joints.
“When these cells see TNF-alpha, they rapidly activate a therapy that reduces inflammation,” Dr. 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.
“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.”
With an eye toward further applications of this approach, “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,” Dr. Brunger added.
Brunger JM, Zutshi A, Willard VP, Gersbach CA, Guilak F. Genome engineering of stem cells for autonomously regulated, closed-loop delivery of biologic drugs. Stem Cell Reports. Published online April 27, 2017.