Shriners Children’s St. Louis Leads Way in Rheumatoid Arthritis Treatment

As director of research at Shriners Children's St. Louis, it may come as a surprise that Farshid Guilak, Ph.D., has dedicated his career to curing arthritis.

Dr. Guilak, the co-director of the Washington University Center of Regenerative Medicine and a biomedical engineer who has studied joint diseases for the past 35 years, joined the team in the Gateway City a little more than five years ago to continue developing treatment for a variety of illnesses including osteoarthritis, something traditionally thought of as an old-age disease.

Children are far from excluded from a debilitating disease that Dr. Guilak said can rob them of their ability to just be kids, in part because it can be difficult and painful to treat. He and his team hope to change that.

Arthritis Impacts Kids Too

Building on prior breakthroughs – and with a goal of developing rheumatoid arthritis therapies that have minimal side effects – Dr. Guilak and his team have genetically engineered cells that, when implanted in mice, deliver a biologic drug in response to inflammation. The new findings were published online Sept. 1 in the journal Science Advances.

The engineered cells reduced inflammation and prevented a type of damage to bone, known as bone erosion. Rheumatoid arthritis affects about 1.3 million adults in the United States. In children, it is often referred to as juvenile idiopathic arthritis (JIA), and affects over 300,000 children in the United States. Those battling arthritis see their joints swell up, experience significant pain and have associated symptoms like fatigue, depression and some cardiac issues.

“Our laboratory uses what we call a multidisciplinary approach. We study it using engineering, biology, chemistry, materials; all different fields. We try to combine the latest technologies from all different areas so that we can understand arthritis and develop new cures and new treatments for these children who have either inflammatory arthritis like juvenile arthritis or, surprisingly, osteoarthritis. So many children now are getting it for a variety of reasons. It’s almost an epidemic.”

Guilak says children are getting osteoarthritis from sports injuries as well as the rapidly increasing prevalence of obesity, which he called the number one preventable risk factor for the disease. Many children also have hip dysplasia, or deformities in the hip, that lead to rapid development of osteoarthritis.

“Some of our children in the hospital are getting joint replacements in their teens, which is really not something that we want to be doing,” he said. “My goal has been to try to understand these diseases and do our best to develop new cures and new therapies for them in the Shriners hospital.”

Many of those modern therapies involve the administration of biologic drugs. These basically suppress the immune system, but they work in maybe half of the patients. Dr. Guilak said a big issue with these drugs is that dosing is difficult. Plus, if you suppress the immune system, the patients have an increased risk of infection and an increased risk for some cancers. Also, these drugs are expensive. When given sometimes as often as twice a week, the cost can quickly exceed more than $25,000 a year. Perhaps the worse side effect, especially for children, is that repeated injections of these drugs is painful.

Smart Cells and Super Mice

So, where does the solution lie? Potentially with what have affectionately been called “super mice” and SMART cells. The acronym stands for Stem cells Modified for Autonomous Regenerative Therapy, but also aptly describes how they work.

“Our thought was, can we develop a system using living cells and get the cells to create these drugs in your body? In that way, the cells could continuously make and deliver biologic drugs used to combat arthritis,” Dr. Guilak said. “Now, the problem with that is we don’t want drugs gushing out in your body in an uncontrolled manner, but instead, we want them to be highly tuned to the level disease that you have.”

This line of study actually began several years ago, when the team came up with this concept of a SMART cell with reprogramed genetics.

“I compare it to an iPhone, where we basically just put in a little app that senses inflammation and when the cell feels that there’s inflammation out there, it turns on the drug,” Dr. Guilak said. “And when the inflammation subsides, it stops making the drug.”

Arthritis and similar diseases result in flare ups, where the disease increases in intensity. Individuals suffering from the disease may have a few hours of increased inflammation, but it can also last for days. They only need drugs for a certain period of time, so they created cells that can actually do that. The research team created a tiny disk about a quarter inch in diameter and about a millimeter thick that they can then put under the skin. It can sit there dormant for months and not do anything. But if it senses inflammation, it turns on the drug that fights arthritis.

“Although biologics have revolutionized the treatment of inflammatory arthritis, the continuous administration of these drugs often leads to adverse events, including an increased risk of infection,” Christine Pham, M.D., director of the division of rheumatology, said in a prepared release from Washington University. “The idea of delivering such drugs essentially on demand in response to arthritis flares is extremely attractive to those of us who work with arthritis patients, because the approach could limit the adverse effects that accompany continuous high-dose administration of these drugs.”

“This will take a few years. But if this works, then what we could do is eliminate injections multiple times a week for these inflammatory diseases, which is very difficult for the children. We could just put an implant under their skin and have the drugs that they need to treat arthritis just delivered whenever they need them, automatically in a manner that doesn’t cause side effects,” Dr. Guilak said. “Now it’s a little bit of science fiction, and we have some work to do, but we have all the pieces in place, and hopefully we will get to that eventually.”

Limitless Applications

The next step is test to see how long these implants will survive and how well they work.

“We tested them for a few months, which is great, but we’d ideally like to have them last a year or two inside the body,” Dr. Guilak said. “Then we want to make more complex versions of this because it is not just one molecule that causes inflammation. It’s a whole family of molecules. So we can make implants that treat each different molecule, but very specifically. And that’s sort of the smart part of those cells is they can sense one versus the other.”

Dr. Guilak said much of the research success goes to how the team is built and the unique partnership between Shriners Children’s and Washington University. He oversees the laboratory, one of the largest muscular skeletal research labs in the country focused on pediatric diseases, made up of about 30 lab members, including graduate students at Washington University, postdoctoral fellows and staff.

“Our team is really important for doing this type of project. These are huge projects, and it takes a number of people working together for years. This project took four or five years with nearly a dozen people working on it. But it’s really one team and one group. We’re able to attract the brightest, most talented investigators in the area to work on these projects. And so our strategy has been to build these collaborative teams where everyone is interested in solving the same problem, and they all put their egos aside and say, alright, here’s how we need to solve it by working together.”

Dr. Guilak said the unique atmosphere at Shriners Children's St. Louis also makes this possible.

“It is just a wonderful job. I love the Shriners, their generosity, their enthusiasm,” Dr. Guilak said. “The other really incredible part about our job is that we are actually in the hospital. So when we walk into the lab, we see the children who have come from all over the world to receive treatment at Shriners. And it’s really wonderful motivation for us to know why we’re doing what we’re doing.”

In addition to Shriners Children's, this work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Institute on Aging, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Cancer Institute and the Office of the Director of the National Institutes of Health.

Additional support came from the Nancy Taylor Foundation for Chronic Diseases, the Arthritis Foundation and the Phillip and Sima Needleman Fellowship from the Washington University Center of Regenerative Medicine.

Read the full research article, and read a release from Washington University.