Osteoarthritis, the third-most common cause of disability in the United States, is currently incurable. This degenerative disease causes joint tissues to break down over time, often leading to debilitating chronic pain.
“With rheumatoid arthritis, an autoimmune disease in which the abnormal biology is more easily defined, there have been all sorts of advances in the last 20 years. With osteoarthritis, we haven't made any progress,” says Thomas Kremen, MD, an orthopedic surgeon and clinician-scientist faculty member at UCLA’s David Geffen School of Medicine. He says he is all too familiar with how osteoarthritis can impair his patients’ quality of life.
For the 32.5 million Americans suffering from osteoarthritis, surgery offers an imperfect treatment, and the overall economic burden of the disease in the United States is estimated at more than $100 billion annually.
With that burden in mind, researchers at UCLA Health are collaborating with teams at Duke Health and Boston’s Children’s Hospital to develop an affordable, injectable therapy to regenerate damaged joints.
The multi-institutional team is one of five funded by the Advanced Research Projects Agency for Health (ARPA-H), an agency within the U.S. Department of Health and Human Services (HHS). The goal of the ARPA-H Novel Innovations for Tissue Regeneration in Osteoarthritis (NITRO) program is to “create and commercialize injectable and implantable regenerative therapies for osteoarthritis.”
Working alongside Dr. Kremen, the UCLA Department of Orthopaedic Surgery research team also includes Karen Lyons, PhD, professor and vice-chair for research, and Weiguang Wang, PhD, an assistant research faculty member. In a collaborative effort translating bench science into a bedside treatment, all three of these investigators have developed innovative technologies that, when combined, lead to a novel multimodal treatment approach.
“With a disease as complex as osteoarthritis, it is unlikely that there is going to be a cure with a single drug,” Dr. Lyons says. “What is unique about our team is that we have a group of collaborators with many different ideas, and we’re putting them together to create a more holistic solution to this problem.”
Taking a cue from the embryo
In the lab of Dr. Lyons, who is a developmental biologist, researchers have been studying the signaling pathways that cause cartilage to develop in utero during early development.
Once Drs. Lyons, Wang and Kremen connected, the scientists wondered if they could target the same pathways to regenerate damaged cartilage and bone tissue in adult patients suffering from osteoarthritis.
“Many of the same pathways that were used during early development are redeployed when tissues try to repair themselves,” Dr. Lyons says.
While developmental biology studies offer important clues about which pathways might be best targeted to treat osteoarthritis, there are significant differences between newly formed joints and adult joints. Those include barriers like inflammatory pathways and a diminished pool of cells capable of regeneration and repair in adults.
To test how well these pathways might be employed to repair joint degeneration, the UCLA research team has used both genetic and pharmacologic approaches in mouse models, to identify several drugs that have the potential to repair articular cartilage and its underlying bone.
The ARPA-H NITRO project will allow the UCLA Health team and their collaborators — who have also identified potential drugs that can slow osteoarthritis progression — to identify combinations of these specialized drugs and optimized drug delivery approaches.
In addition to using animal models, the researchers will also be testing their strategies on a so-called “joint-on-a-chip” platform, which mimics the healthy or diseased features of joints inside of the body.
Ultimately, the research team plans to develop three separate types of injectables that patients would receive once per year: One that targets joint tissues; another that targets adjacent bone; and a systemically administered drug that could treat cartilage tissues in patients who have osteoarthritis in multiple joints.
At the end of five years, Dr. Kremen says, the researchers plan to have completed the testing of these treatments in phase I clinical trials which will be conducted at UCLA.
“ARPA-H is really focused on commercialization and affordability,” Dr. Kremen says. “They have an ambitious timeline, because they, and we, want to get these therapies into people as soon as possible.”
