Genetically engineered cartilage delivers anti-inflammatory drugs in response to knee activity

Working to develop new treatments for osteoarthritis, researchers at the University of Washington School of Medicine in St. Louis are looking to work. Louis has genetically engineered cartilage to deliver an anti-inflammatory drug in response to activity similar to knee flexion or other movements that stress joints.

Early symptoms of osteoarthritis include pain in response to such movements -; movements involving component mechanical loading. Joint pain that comes with bending or lifting can make it difficult to perform normal activities. But by altering genes in cartilage cells in the laboratory, the researchers have been able to program them to respond to the mechanical stress associated with movement and pressure by extracting drug to combat inflammation.

The study is published online Jan. 27 in the journal Advances in science.

Drugs such as ibuprofen and naproxen that relieve joint pain and lower systemic inflammation are the main treatments for osteoarthritis pain, but there are no treatments that prevent damage in joints of patients with this debilitating form of arthritis. We have developed a new field of research called mechanogenetics, where we can engineer cartilage cells to respond to the mechanical loading of the component. Every time cells are under that pressure, they take an anti – inflammatory, biological drug to reduce inflammation and limit arthritis – related damage. “

Farshid Guilak, PhD, Principal Investigator, Mildred B. Simon Professor, Orthopedic Surgery

With his team, Guilak, co-director of the University of Washington Center for Regenerative Medicine and director of research at Shriners Children’s Hospitals -; Cape St. Louis, first experiments in the laboratory using cartilage cells from pigs to find out how those cells feel when under mechanical pressure.

“Examining these cells in the laboratory, we were able to identify key pathways in the cells responding to stress from loading and the gene circuits in cartilage activated by loading mechanics, ”said co – author Robert J. Nims, PhD, a postdoctoral researcher in the Guilak laboratory.

Similar to the friction sensor on a smartphone, cartilage cells sense when pressure is applied, and the inflammation associated with too much arthritis pressure causes cartilage to break down. The cells developed in these experiments, however, responded to that stress by ingesting an anti-inflammatory drug that prevented cartilage damage.

“We modified fragments of DNA in the cells to tell them to do something different than normal when they feel loads,” Guilak said. “That is, to make an arthritis-fighting drug.”

“It’s like turning on a light,” said co-author Lara Pferdehirt, a biomedical engineer and graduate research assistant at Guilak’s lab. “With light, you turn on a switch, and a light switch turns on. But in this case, the switch is a complementary mechanical load, and the bulb is the anti-inflammatory drug.”

The cells were engineered to release an interleukin-1 receptor antagonist -; a drug called anakinra (Kineret) that is used to treat rheumatoid arthritis and shows promise for the treatment of post-traumatic osteoarthritis that occurs after a joint injury. Preliminary studies of the drug in patients with osteoarthritis have shown that it is safe but ineffective when it has been introduced into a joint only once. Guilak believes that because of its proper functioning, the drug must be released into arthritic joints over longer periods of time, while mechanical loading occurs.

“This drug is unlikely to work unless delivered continuously for years, which may be why it has not worked well in clinical trials involving patients with osteoarthritis,” he said. “In our experiments in cells in the laboratory, we used the existing signaling systems in the cartilage cells that we engineered so that they could release the drug whenever it was needed. Here, we use synthetic biology to create an artificial cell type that we can program to respond to what we want it to respond to. “

In addition to reducing inflammation in arthritic joints, having specialized cartilage cells delivers the drug only when and where needed it should be possible to avoid associated side effects. to long-term delivery of a strong anti-inflammatory drug to the entire body. These side effects can include stomach pain, diarrhea, muscle weakness and hair loss.

Guilak’s team plans to use the same technique to modify other types of cells to produce different drugs.

“We can create cells that automatically deliver pain relief drugs, anti-inflammatory drugs or growth factors to regenerate cartilage,” Guilak said. “We believe this strategy could be a framework for doing what we can to program cells to deliver treatments in response to a number of medical problems.”