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Reversing OA—New Treatment on the Horizon

May 5, 2017
Intra-articular injection of an agent to clear away senescent cells from injured knees was found to reduce pain and improve healing in a mice model.

Interview with Jennifer H Elisseeff, PhD

It is known that senescent cells (SnCs) accumulate in joints with age and following joint injury, but now researchers have shown they may play a role in the development of osteoarthritis (OA).1

“The presence of senescent [chondrocytes] in diseased cartilage has been known for a while—they were found in tissue from patients undergoing total knee arthroplasty, but their role was unknown,” said Jennifer H Elisseeff, PhD, from the Department of Biomedical Engineering, at Johns Hopkins University in Baltimore, Maryland.

However, recent studies have started to explore the role of senescent cells in age-related chronic diseases, said Dr. Elisseeff. This recent study suggests there may be some bright prospects on the horizon for developing a new treatment for OA to selectively target SnCs and affect the disease course of OA in humans.

In their study, Dr. Elisseeff and colleagues transected the anterior curciate ligament (ACLT) in mice (p16-3MR transgenic mouse model) to show more SnCs in the articular cartilage and synovium. By removing these SnCs after injury, the research team was able to reduce pain related to post-traumatic OA, but also attenuate the disease’s course and promote cartilage development.1

The research could open the doors to developing a new systemic treatment for OA, which according to Dr. Elisseeff, is currently “very realistic.” “This is pretty amazing and we are very excited about it,” Dr. Elisseeff told Practical Pain Management. Unity Biotechnology is now taking this research forward to explore the possibility of creating new therapies using SnCs as a treatment target. “This is a smart team and I have great confidence in their ability to get a drug out there soon to help people,” said Dr. Elisseeff.

Researchers have identified a new target for reducing osteoarthritis pain—senescent cells.

Senescent Cells: A Treatment Target for OA

SnCs accumulate in vertebrae tissues as part of the aging process and contribute to the pathologies of age-related diseases.2-4 OA, which is characterized by the degeneration of articular cartilage, can become a significant source of pain, disability, and loss of quality of life for patients.5

In the study, Dr. Elisseeff and her colleagues were able to prove that SnCs do develop following an articular joint injury. After inducing post-traumatic OA into transgenic mice, the researchers could see the mRNA levels rise in specific factors related to the senescence-associated secretory phenotype (SASP), specifically Cdkn2a, Cdkn1a, and interleukin (IL)-6.

These same mice subsequently developed post-traumatic OA, showing signs of cartilage thinning, surface irregularities, and induction of type II collagen degradation, as well as OA-induced pain.

Because the researchers used transgenic mice, they were able to selectively remove the SnCs that developed following the ACLT injury. By clearing the SnCs, researchers could see inhibited articular corrosion, as well as decreased pain associated with the ACLT injury. Specific inflammatory markers matrix metalloproteinase 13 (Mmp13) and IL-1β (Il1b), which are associated with OA disease and tissue degradation,6 also appeared to decrease.

A New Prospective Treatment?

According to the researchers, the data showed that removing SnCs in the articular cartilage and synovium of the knee joint, even after OA symptoms already develop, can reduce the impact of the disease’s progression and actually facilitate a prochondrogenic environment.

The researchers were able to remove the SnCs pharmaceutically, through an intra-articular injection of UBX0101, a senolytic that appeared to effectively clear SnCs with a single 0.2 mm dose. In fact, after injecting mice with this agent, researchers could see greater expression of Col2a1 and Acan gene, which according to the researchers, would indicate new cartilage growth.

The researchers also tested how well the agent could perform in mice with later-stage OA, injecting the mice with the agent 42 days after the initial ACLT injury. The agent showed similar success. After 2 weeks of intra-articular injections, the number of non-SnCs with nuclear HMGB1 increased and the mice appeared to show reduced OA-induced pain. In fact, even with this late-stage treatment, the mice showed similar osteophyte formation relative to the vehicle-treated control group, the authors noted.

Interestingly, the researchers also explored how well the removal of SnCs could benefit older aged mice. This is a topic of interest, considering aging can have a significant impact on how spontaneous and injury-induced OA can develop in mice and humans, alike.7,8

Indeed, the researchers found that a more severe form of OA seemed to develop in aged mice. When given the same treatment regimen that was given to the younger mice, older mice did show a positive response: reduced OA-induced pain, reduced expression of disease-associated factors (Cdkn2a, Cdkn1a, IL-6, and Mmp13), and reduced gene expression levels (Cdkn1a and Mmp13). However, unfortunately for the aged mice, they didn’t show the same increased expression of prochondrogenic genes (Col2a1 and Acan) that was seen in younger mice receiving the treatment.

Various authors of this study own equity in Unity Biotechnology, the company mentioned in this article. These authors include Judith Campisi, Remi-Martin Laberge, Yan Poon, Darren J Baker, Jan M van Deursen, Marco Demaria, Nathaniel David, and Dr. Elisseeff. Johns Hopkins University and Unity Biotechnology own intellectual property related to the research. Ok Hee Jeon, Chaekyu Kim, and Dr. Elisseeff are inventors of Johns Hopkins University intellectual property licensed to Unity Biotechnology.

Last updated on: June 1, 2017
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