Targeting undying cells: A new approach to back pain treatment

The World Health Organization’s list of the leading causes of death features feared illnesses like ischemic heart disease and stroke. Many of these conditions also appear in the top 10 causes of disability-adjusted life years — the maladies that make people’s lives most painful and miserable. One condition that only features in the second list is back and neck pain. Back pain is the number one reason patients see primary physicians, said Lisbet Haglund, an orthopedics researcher at McGill University. Existing treatments are rarely effective. “We don't have any disease-modifying drugs,” she added.

Haglund’s new study, published in Science Advances, suggests a new pharmacological treatment could reach the root of back pain by targeting senescent cells — zombies that refuse to die (1).

That’s the most important finding, I would say, of the grant: that we could reduce back pain in these animals after a fairly short treatment period.
- Lisbet Haglund, McGill University

The role of senescent cells in chronic pain

Senescence is a stress-induced state linked to anti-tumor mechanisms, said Paul Robbins, a researcher in aging at the University of Minnesota who was unaffiliated with the study. Senescent cells don’t divide but also resist apoptosis, the managed process of cell death (2). As people age, cells accumulate damage and their telomeres shorten. Both factors increase the risk of cancer. As a protective mechanism, cells enter senescence and release pro-inflammatory molecules that signal to immune cells that they need to be destroyed. This system is thought to effectively reduce cancer risk in young people, but during aging, the immune system weakens and the balance tilts, said Robbins. “You get to a point where the immune system is not that effective at clearing these senescent cells,” he said.

Senescent cells that accumulate in intervertebral discs (IVDs) contribute to back pain through increased local inflammation (3). Anti-senescence drugs, called senolytics, target numerous aspects of cell function. Some drugs boost p53, a protein called the “guardian of the genome” due to its tumor-suppressing and cell cycle-regulating functions. One such compound is called RG-7112. Researchers previously tested the drug at high doses in cancer patients, but it induced severe gastrointestinal side effects (4).

A previous publication from Haglund’s group demonstrated the senolytic effects of RG-7112 and another molecule called o-vanillin (5). This is a natural compound derived from curcumin, the chemical that gives turmeric its sunshine-yellow tint. In the new paper, they tested how well RG-7112 and o-vanillin reduced back pain in a mouse model of the condition.

Promising results from a new combination therapy

The team showed that mice given RG-7112 or o-vanillin had less pain and inflammation, fewer senescent cells in the IVDs, and improved bone quality and degeneration scores compared to control mice after just eight weeks of treatment. Importantly, the effect was heightened when the drugs were given in combination. “That’s the most important finding, I would say, of the grant: that we could reduce back pain in these animals after a fairly short treatment period,” said Haglund.

She added that because IVDs have little nerve or blood vessel innervation, the team was unsure whether the drugs would reach the senescent cells in the area. But o-vanillin and RG-7112’s efficacy through oral administration was a positive sign that they could do so. The team used RG-7112 in a lower dose, mitigating the side effects previously shown in cancer trials.

Challenges and the future of treatment for back pain

The team now wants to improve the pharmacokinetic profile of o-vanillin, which is cleared from the body rapidly. A longer half-life would give the drug more time to enter the IVD, said Haglund.

These promising results in mice will not necessarily translate to efficacy in humans. Back pain is a very heterogeneous condition. “We see people with degeneration of the spine quite commonly with no symptoms at all,” said Aidan Cashin, a pain researcher at Neuroscience Research Australia, who recently coauthored a massive metareview of available treatments for back pain and was not associated with the new study (6). Haglund agrees that targeting the correct back pain patients will be critical to future success for any RG-7112-o-vanillin combination treatment. She added that the field currently struggles to stratify patients. “I think it is one reason why a lot of treatment fails, because we're not picking the right patients to treat,” she concluded.