A potential long-lasting gene therapy for chronic nerve pain

What is it about?

Chronic nerve pain can be difficult to treat. Existing medicines do not always provide enough relief, and some can cause unwanted side effects or lead to dependence. In this study, we investigated a new approach that could potentially provide much longer-lasting pain relief after a single treatment. We focused on a protein called PICK1, which helps control communication between nerve cells and has been linked to the development of pain. We developed peptides that can block PICK1. We then used a harmless virus commonly used in gene therapy, called an AAV, to deliver the instructions for making these peptides into nerve cells. We tested the treatment in mice with different types of pain, including inflammation-induced and nerve-injury-induced pain. We found that blocking PICK1 reduced abnormal sensitivity to touch and other signs of pain. Importantly, the effect was not just temporary: in one nerve-injury model, the treatment continued to reduce pain for up to one year. We also investigated where in the nervous system the treatment needed to act. We found that delivering the PICK1-blocking peptide to sensory nerve cells in the dorsal root ganglia was enough to produce pain relief. The treatment worked in both male and female mice, and we did not observe obvious harmful side effects in our experiments. To better understand how the treatment works, we examined changes in proteins inside these sensory nerve cells. Our results point to changes in several molecules involved in controlling nerve activity and pain, including a protein called protein kinase C alpha. These findings may help explain why blocking PICK1 can reduce pain. Finally, we examined human tissue and found that PICK1 is present in human sensory nerve cells and that the peptide can interact with its target. This is an important step because it suggests that the biological target we studied in mice also exists in humans. Overall, our study provides early evidence that AAV-delivered PICK1 inhibitors could potentially become a long-lasting treatment for chronic neuropathic pain. However, our work was carried out primarily in mice. The findings do not yet show that the treatment is safe or effective in people, and substantial further research will be needed before this approach could be tested as a treatment for patients.

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Photo by julien Tromeur on Unsplash

Photo by julien Tromeur on Unsplash

Why is it important?

Chronic pain remains a major clinical challenge, particularly neuropathic pain, for which current treatments often provide incomplete relief and may require long-term medication. There is a pressing need for new approaches that can provide effective, durable pain relief without the limitations associated with existing therapies. What makes our work particularly distinctive is that we combine a new molecular target, a gene-therapy approach, and the potential for long-lasting pain relief. We developed PICK1-inhibitory peptides and used an AAV-based approach to deliver them directly to sensory neurons involved in pain. Rather than repeatedly administering a conventional drug, this strategy is designed to enable the treated neurons to produce the therapeutic peptide themselves. A particularly striking finding is the durability of the effect. In our nerve-injury model, a single treatment was able to reduce pain-related sensitivity for up to one year. This raises the possibility of developing a treatment that could provide prolonged relief from chronic pain after a single administration. Our study is also timely because advances in gene therapy are making it increasingly possible to target specific cell populations and develop treatments that act locally within the nervous system. By targeting sensory neurons in the dorsal root ganglia, our approach may offer a way to interfere with pain signalling while potentially limiting exposure to the rest of the body. Importantly, we provide evidence that the target is relevant to humans: we detected PICK1 protein in human sensory neurons and demonstrated interaction of our inhibitory peptide with its target. While substantial work remains before this approach can be considered for clinical use, these findings provide an important bridge between experimental pain models and potential human translation. We believe our work will be of broad interest because it presents a fundamentally different way of thinking about the treatment of chronic pain: instead of repeatedly suppressing pain with systemic medication, it explores whether a single, targeted genetic treatment can produce sustained changes in the neurons that drive pain. If successfully translated, this strategy could ultimately contribute to a new generation of long-lasting treatments for chronic neuropathic pain.

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