A Cure for Osteoarthritis?
In April of this year, the U.S. government awarded millions of dollars to scientists to develop novel joint regeneration therapies to treat and perhaps cure osteoarthritis (OA), the third most common cause of disability in America. Older adults are disproportionately impacted by this degenerative bone disease that affects more than 32 million people. The physical symptoms such as pain and stiffness, trouble using stairs and opening jars, and sometimes just walking can be quite debilitating. But the consequences of OA are more than just physical.
The disease can take significant toll on emotional and social well-being. For example, people who have chronic OA pain may have to give up doing things they love, such as pickleball, gardening, or playing instruments. Difficulty participating in social and recreational activities can lead to feelings of isolation and loneliness. All this can spiral down into a sedentary life, raising risk for obesity, heart disease and diabetes. Chronic pain and physical limitations also can lead to feelings of frustration, sadness, anxiety, and depression. For these reasons and others, researchers at UCLA and elsewhere have been striving to find better treatments and cures for OA.
“There is the obvious challenge of optimizing the science of the treatment to make sure it is effective in all types of patients. But this process also requires obtaining funding in a fiercely competitive funding landscape, navigating the regulatory environment, and making the therapy available in the relatively near-term future,” explains Thomas Kremen, MD, an orthopedic surgeon, and clinician-scientist faculty member at UCLA’s David Geffen School of Medicine. “The commitment of significant funding greatly accelerates the pace of the research and allows for the implementation of therapies in my patients much faster than the traditional timeline for developing novel therapeutics.”
A MultiCenter Effort
UCLA Health is part of a multi-institution research team receiving the contract for up to $33 million from the federal Advanced Research Projects Agency for Health (ARPH-A) for the development of new treatments specifically focused on joint regeneration for OA. UCLA’s portion of the award will support the development of novel therapies, with the goal of completing an FDA phase 1 clinical trial within the next five years.
This multi-institution team, which also includes researchers from Duke University and Boston Children’s Hospital, is one of five selected to develop innovative forms of regenerative medicine–including affordable injectable and implantable therapies – that can regenerate joint tissue damaged by OA.
More Than Wear and Tear
The cause of OA has primarily been thought to be physical wear and tear, but it’s more complicated than that. “OA is multifactorial with contributions from our genetic backgrounds, environmental exposures, history of traumatic injuries, each patient’s individual activity level, medical comorbidities, and age,” explains Dr. Kremen. “While high-impact activities are generally thought to increase wear and tear in the joint, a lack of activity is also associated with joint degradation and progression of symptoms.”
Current recommendations to slow progression of OA include lifestyle behaviors such as not smoking, losing weight, and treating medical comorbidities such as diabetes. “As challenging as it is to lose weight, for each pound we lose that equates to 4 pounds of force removed from each knee joint, and patients really notice improved mobility and decreased joint pain when they do lose weight.”
While pain and stiffness also are symptoms of rheumatoid arthritis (RA), it is far less common than OA and a distinctly different disease process. RA affects about 1.3 million adults, women more than men, and tends to begin between the ages of 30 and 50. Neither OA nor RA currently has a cure.
“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 Dr. Kremen.
Joint replacement and surgeries for OA offer imperfect treatments. While there is no age limit for joint replacement per se, preexisting conditions may make the process and recovery more complicated for older adults. Joint injections work for some people, others not so much. And then there’s all the marketing hype surrounding regenerative stem cell treatments, of which none are currently FDA-approved.
“We have much work to do to characterize the mechanisms by which these cells may influence the biology of healing,” says Dr. Kremen. “Like many things in life, if what a clinician is claiming about a cell-based therapy sounds too good to be true, then it probably is not true. If you are being offered a stem cell therapy or a birth product-based therapy (e.g. umbilical cord blood, placental tissue, or amniotic membrane derived products), this should only be done in the setting of a clinical trial.”
Insights Into Cartilage Regeneration
Tissue regeneration is a burgeoning field. 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. All three of these investigators have developed innovative technologies that, when combined, lead to a novel multimodal treatment approach.
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.
In addition to using animal models, the researchers will 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.
Moving Forward
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 OA 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.”
“You gain immediate feedback from a knowledgeable physical therapy professional,” says Dr. Kremen.
Physical activity strengthens muscles and bones. If you have pain with one activity, Dr. Kreman suggests trying another activity that is known to be lower impact. For example, instead of running you try brisk walking, biking, or an elliptical machine. If those cause pain that is not tolerable, try something even lower impact like swimming or walking in the pool.
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