Stem cells edited to fight arthritis
Goal is vaccine that targets inflammation in joints
by Jim Dryden • April 27, 2017
Using new gene-editing technology, researchers have rewired mouse stem cells to fight inflammation caused by arthritis and other chronic conditions. Such stem cells, known as SMART cells (Stem cells Modified for Autonomous Regenerative Therapy), develop into cartilage cells that produce a biologic anti-inflammatory drug that, 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, N.C. 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.
The research is available online April 27 in 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 and a professor of orthopedic surgery at Washington University School of Medicine. “To do this, we needed to create a ‘smart’ cell.”
Many current drugs used to treat arthritis — including Enbrel, Humira and Remicade — attack an inflammation-promoting molecule called tumor necrosis factor-alpha (TNF-alpha). But 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,” said Guilak, also a professor of developmental biology and of biomedical engineering and co-director of Washington University’s Center of Regenerative Medicine. “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, 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 and a postdoctoral fellow in cellular and molecular pharmacology at the University of California, San Francisco… Continue reading....
A twisted ankle, broken hip or torn knee cartilage are all common injuries that can have medical ramifications long after the initial incident that causes them. Associated pain, inflammation, joint degeneration and even osteoarthritis can sideline a variety of different people: athletes, weekend warriors and patients who are either aging or inactive.
A team from Washington University in St. Louis was awarded $1.7 million from the National Institutes of Health (NIH) to develop a new therapeutic treatment that can deliver disease-modifying compounds in a manner to delay the development of inflammation, joint degeneration and arthritis with all the associated discomfort, disability and pain.
“We’re starting to see that many areas can’t be reached via oral drug delivery,” said Lori Setton, the Lucy & Stanley Lopata Distinguished Professor of Biomedical Engineering at the School of Engineering & Applied Science. “For example, synovial joint fluid in the knee is almost optimized to rapidly clear compounds out of the joint. So we’re trying to trick the joint into being a good host for the therapeutic drugs we are delivering.”
Setton, whose lab focuses on the role of mechanical factors in the breakdown and repair of soft tissues, said an intracellular compound called nuclear factor kappa B (NF-kB) is a main culprit in cellular breakdown, inflammation and pain after an injury. She’s working in the lab on a new solution using silk to deliver two specific molecules that can inhibit NF-kB at the site of a fracture or injury in an effort to stave off long-term joint damage.
“Silk naturally doesn’t interact with water, and, when you mix it with these molecules that also don’t interact with water, they bind to each other very strongly,” Setton said. “We believe these selective compounds are therapeutically effective, but we’ve never been able to get them to their target site. By delivering them with the silk, we hope to get large doses to the target site with low toxicity and to have them remain in that compartment for longer periods of time.”
In preliminary work with Tufts University investigator David Kaplan, Setton showed that model compounds can reside in the joint space about five times longer if delivered with silk microparticles than if delivered alone. Silk is an attractive delivery vehicle because of its long history of safe clinical use, and Kaplan has received NIH support to promote translational uses of silk for medical and other applications. It was initial work in delivering silk to the knee joint that drove Setton to identify a suitable, disease-modifying compound for treatment of arthritis through collaborations with the Musculoskeletal Research Center at the Washington University School of Medicine.
Setton and her co-investigators at the School of Medicine — including Yousef Abu-Amer, professor of orthopaedic surgery; Farshid Guilak, professor of orthopaedic surgery; and Gabriel Mbalaviele, associate professor of medicine in the Division of Bone and Mineral Diseases — soon will start testing the new delivery system in animal models.
“Delivering drugs orally to combat NF-kB-mediated problems at specific locations in the body, such as the injured knee, can be associated with harmful biological functions,” Abu-Amer said. “So this type of site-targeted approach to inhibit elevated NF-kB is essential if we want to provide effective treatment to the targeted site.”
According to Setton, the enhanced drug-delivery system has the potential to prevent the onset and progression of joint damage in patients suffering from acute injuries, like minor joint fractures, ligament or meniscal tears.
“Patients with joint trauma tend to go on to develop osteoarthritis at a higher rate compared to someone who doesn’t have the injury,” Setton said. “It’s a whole different type of arthritis development that we don’t know a whole lot about, but we believe we can intervene early with new drug delivery and treatments, and prevent onset at a later stage.”...
With a goal of treating worn, arthritic hips without extensive surgery to replace them, scientists have programmed stem cells to grow new cartilage on a 3-D template shaped like the ball of a hip joint. What’s more, using gene therapy, they have activated the new cartilage to release anti-inflammatory molecules to fend off a return of arthritis.The technique, demonstrated in a collaborative effort between Washington University School of Medicine in St. Louis and Cytex Therapeutics Inc. in Durham, N.C., is described July 18 in Proceedings of the National Academy of Sciences.The discovery one day may provide an alternative to hip-replacement surgery, particularly in younger patients. Doctors are reluctant to perform such operations in patients under age 50 because prosthetic joints typically last for less than 20 years. A second joint-replacement surgery to remove a worn prosthetic can destroy bone and put patients at risk for infection.“Replacing a failed prosthetic joint is a difficult surgery,” said Farshid Guilak, PhD, a professor of orthopedic surgery at Washington University. “We’ve developed a way to resurface an arthritic joint using a patient’s own stem cells to grow new cartilage, combined with gene therapy to release anti-inflammatory molecules to keep arthritis at bay. Our hope is to prevent, or at least delay, a standard metal and plastic prosthetic joint replacement.”...
Scientists in the US have determined that omega-3 consumption could help to improve the joint health of patients with osteoarthritis.
Carried out by Duke University in North Carolina, the study – published in the Annals of the Rheumatic Diseases – has shed further light on the established relationship between obesity and arthritis, suggesting that unhealthy dietary fats may exacerbate osteoarthritis symptoms.
The team examined a sample of mice with osteoarthritis of the knee caused by injury to the joint, all of whom were fed one of three high-fat diets – one rich in saturated fat, one high on omega-6 fatty acids, and one that supplemented a high omega-6 intake with a small amount of omega-3.
It was found that arthritis was significantly associated with the mice’s diets, but not with body weight – a noteworthy development, given that it is often understood that the impact of obesity on arthritis is caused by the additional pressure on load-bearing joints.
The mice that ate diets high in saturated fat or omega-6 fatty acids experienced significant worsening of their arthritis, while mice consuming supplements of omega-3 had healthier joints.
Moreover, those receiving omega-3 had an enhanced capability to heal wounds, further underlining the health benefits of this form of fatty acid.
Dr Farshid Guilak, professor of orthopaedic research at the Duke University Medical Center, said: "Our results suggest that dietary factors play a more significant role than mechanical factors in the link between obesity and osteoarthritis."...
Duke researchers use gene therapy to direct stem cells into becoming new cartilage on a synthetic scaffold even after implantation into a living body.
By combining a synthetic scaffolding material with gene delivery techniques, researchers at Duke University are getting closer to being able to generate replacement cartilage where it’s needed in the body.
Performing tissue repair with stem cells typically requires applying copious amounts of growth factor proteins—a task that is very expensive and becomes challenging once the developing material is implanted within a body. In a new study, however, Duke researchers found a way around this limitation by genetically altering the stem cells to make the necessary growth factors all on their own.
They incorporated viruses used to deliver gene therapy to the stem cells into a synthetic material that serves as a template for tissue growth. The resulting material is like a computer; the scaffold provides the hardware and the virus provides the software that programs the stem cells to produce the desired tissue.
The study appears online the week of Feb. 17 in the Proceedings of the National Academy of Sciences.
Farshid Guilak, director of orthopaedic research at Duke University Medical Center, has spent years developing biodegradable synthetic scaffolding that mimics the mechanical properties of cartilage. One challenge he and all biomedical researchers face is getting stem cells to form cartilage within and around the scaffolding, especially after it is implanted into a living being....
A Duke research team has developed a better recipe for synthetic replacement cartilage in joints.
Combining two innovative technologies they each helped develop, lead authors Farshid Guilak, a professor of orthopedic surgery and biomedical engineering, and Xuanhe Zhao, assistant professor of mechanical engineering and materials science, found a way to create artificial replacement tissue that mimics both the strength and suppleness of native cartilage. Their results appear Dec. 17 in the journal Advanced Functional Materials.
Articular cartilage is the tissue on the ends of bones where they meet at joints in the body – including in the knees, shoulders and hips. It can erode over time or be damaged by injury or overuse, causing pain and lack of mobility. While replacing the tissue could bring relief to millions, replicating the properties of native cartilage — which is strong and load-bearing, yet smooth and cushiony — has proven a challenge....