Researchers led by the University of Pennsylvania have engineered a brain-targeted gene therapy that dials down pain in mice without activating reward pathways linked to addiction. The work could lay the groundwork for non-addictive treatments for chronic pain.
For millions of people living with chronic pain, relief often comes with a dangerous trade-off: opioid drugs that can ease suffering but carry a high risk of addiction and overdose. A new preclinical study suggests a different path may be possible.
Researchers led by the University of Pennsylvania have developed an experimental gene therapy that targets pain-processing centers in the brain and appears to provide long-lasting pain relief in mice without triggering the brain’s reward circuits that drive addiction.
The approach, described in the journal Nature, acts like a volume knob that turns down only the pain channel, leaving other brain functions largely untouched. It is still early-stage work in animals, but scientists say it could eventually help people whose lives are dominated by chronic pain.
The team set out with a clear objective.
“The goal was to reduce pain while lessening or eliminating the risk of addiction and dangerous side effects,” co-senior author Gregory Corder, an assistant professor of psychiatry and neuroscience at Penn’s Perelman School of Medicine, said in a news release.
Morphine and other opioid painkillers work by binding to receptors in the brain and spinal cord, dampening pain signals. But because they act broadly across many brain regions, they can also slow breathing, cloud thinking and activate reward pathways that make the drugs highly addictive. Over time, patients can develop tolerance, needing higher doses to get the same relief.
To design a more precise alternative, the team first used advanced imaging to study brain cells that act as pain trackers. By watching how these cells responded when morphine eased pain in animal models, the researchers gained new insight into the specific brain circuits involved in pain relief.
They then built a behavioral testing platform in mice, driven by artificial intelligence, that could monitor natural movements and behaviors and translate them into a readout of pain levels. This AI system helped the scientists determine how much a given treatment actually reduced pain, rather than relying on cruder measures.
Using that readout as a map, the team engineered a targeted gene therapy that mimics the helpful effects of morphine while avoiding its addictive ones. The therapy is designed to deliver an off switch specifically for pain signals in the brain. When activated, it provided durable relief in mice without blunting normal sensation or activating reward pathways associated with addiction.
The work marks a milestone for the field, Corder noted.
“To our knowledge, this represents the world’s first CNS-targeted gene therapy for pain, and a concrete blueprint for non-addictive, circuit-specific pain medicine,” Corder added.
The study is the result of more than six years of research supported by a National Institutes of Health New Innovator Award and other federal and foundation grants. It arrives at a time when the United States continues to grapple with overlapping crises of chronic pain and opioid misuse.
In 2019, hundreds of thousands of deaths worldwide were attributed to drug use, with the vast majority linked to opioids. In Philadelphia, nearly half of residents responding to a recent survey reported knowing someone with opioid use disorder, and one-third said they knew someone who had died from an overdose.
At the same time, chronic pain has been called a silent epidemic. It affects an estimated 50 million Americans and costs hundreds of billions of dollars each year in medical bills and lost productivity, including missed work and reduced earning potential. Many patients feel trapped between untreated pain and the risks of long-term opioid use.
By focusing on the brain circuits that morphine uses to relieve pain, but not the ones that drive craving and dependence, the new gene therapy strategy aims to ease one crisis without fueling another.
The work also highlights how tools like AI can accelerate drug discovery. The mouse behavioral platform allowed researchers to capture subtle changes in posture, movement and other natural behaviors that correlate with pain, then use those patterns to rapidly test and refine potential treatments.
The research team includes scientists from Penn’s Perelman School of Medicine and School of Nursing, as well as collaborators at Carnegie Mellon University and Stanford University. Some authors are listed as inventors on a provisional patent application related to the custom genetic sequences used in the therapy.
The next step is to move the approach closer to human testing. The team is now working with Michael Platt, the James S. Riepe University Professor and professor of neuroscience and psychology at Penn, to advance the research as a potential bridge toward future clinical trials.
Platt emphasized both the promise and the long road ahead.
“The journey from discovery to implementation is long, and this represents a strong first step,” added Platt. “Speaking both as a scientist and as a family member of people affected by chronic pain, the potential to relieve suffering without fueling the opioid crisis is exciting.”
Before any gene therapy for pain could be tested in people, it would need to undergo extensive safety and efficacy studies in additional animal models, followed by regulatory review. Questions remain about how long the effects would last, how best to deliver the therapy and which patients might benefit most.
Still, the concept of a brain circuit-specific off switch for pain offers a glimpse of a future in which treating chronic pain does not have to mean risking addiction.
If the science holds up through further testing, the work could eventually help turn down the volume for people whose pain has been stuck on maximum for years, without forcing them to choose between relief and safety.
Source: Penn Medicine