Over the last decade, the US opioid crisis has highlighted both the prevalence of chronic pain as well as the need for effective, non-addictive pain treatments. David Bennett, a neurobiologist at the University of Oxford, and his team may have found a solution using gene therapy.
“We are interested in gene therapies and in particular, those that can be used to silence sensory neurons in the peripheral nervous system, which are key in driving chronic pain,” said Bennett. “If we can dial down or silence the activity of sensory neurons, we can provide a means to silence or reduce pain, particularly in the context of chronic pain.”
In their recent study, Bennett and his team delivered an engineered protein receptor to sensory neurons to control their activation and thereby alleviate chronic pain (1). Their gene therapy successfully inhibited sensory neurons and relieved various types of pain in mice. Activity in human-derived sensory neurons also decreased after the gene therapy. If successfully translated for human use, a new therapeutic option like this one could be life-changing for the 20 percent of the population who experience chronic pain (2).
If we can dial down or silence the activity of sensory neurons, we can provide a means to silence or reduce pain, particularly in the context of chronic pain.
- David Bennett, University of Oxford
To control the activity of mouse sensory neurons, the team expressed PSAM4-GlyR, a chloride channel activated by the FDA-approved drug varenicline, in sensory neurons in mice. “The most challenging part was designing and using viral vectors to express PSAM4-GlyR in sensory neurons. Sensory neurons can be tricky to target in vivo, but we managed to target them in a variety of ways that were selective,” said Bennett.
They then tested whether they could use the same approach to control the activity of human-derived sensory neurons as well as sensory neurons derived from a patient with chronic burning pain. The team found that PSAM4-GlyR activation successfully inhibited sensory neuron activity in both mouse and human cells, decreasing hyperactivity in the patient-derived cells. It also ameliorated behaviors related to acute, inflammatory, and neuropathic pain in mice.
Luana Colloca, a physician scientist at the University of Maryland, Baltimore who was not involved in the study, is excited about the gene therapy’s potential. “Currently, we treat pain as a symptom, but without truly treating the cause,” said Colloca. “Once this kind of research continues to advance, I think we will learn new strategies to control pain and treat pain.”
Bennett and his team hope to build on their research by investigating how to target specific subpopulations of sensory neurons using PSAM4-GlyR. Restricting its expression would allow researchers to only silence those neurons driving chronic pain.
Beyond specifically targeting the cells of interest, researchers will also need to investigate different methods of delivering PSAM4-GlyR to humans as the techniques they use in mice are too invasive. Injecting the gene therapy into the corticospinal fluid or specifically to the area causing pain both have potential advantages and disadvantages that scientists will need to explore.
“We hope the next generation of chemogenetic tools will come next,” said Bennett.
References
- Perez-Sanchez, J. et al. A humanized chemogenetic system inhibits murine pain-related behavior and hyperactivity in human sensory neurons. Sci Transl Med 15, eadh3839 (2023).
- Rikard, S.M. et al. Chronic Pain Among Adults — United States, 2019-2021. MMWR. Morbidity and Mortality Weekly Report 72, 379-385 (2023).
