While psychedelic drugs may be capturing all the attention when it comes to finding fresh ways to treat neuropathic pain, research with mice has suggested a peptide approach may also be effective.
Using a short lipidated peptide (SLiP) developed by Mimetic Medicines disrupted a crucial voltage-gated sodium channel (Nav1.8) interaction by reducing the number of these channels in the cell membrane in mice, according to research published Oct. 6 in Cell Reports Medicine.
Nav1.8 channels are primarily expressed in sensory neurons of the dorsal root ganglion, which sits along the spinal cord. These neurons relay sensory information from the body’s periphery to the central nervous system (CNS) so the brain can recognize the signal and decide how to act.
In neuropathic pain, these neurons are dysfunctional because they are in a state of hyperexcitability. This is characterized by an increase in Navs at the cell surface, causing the cells to become overly sensitive and fire more easily, sending constant painful signaling to the CNS, the main symptom of neuropathic pain.
“Nav 1.8 still withholds so much potential as a target for treating chronic pain,” Mimetic Chief Scientific Officer Rasheen Powell, Ph.D., told Fierce in an interview. “This paper does set the groundwork for everyone to say that we need to move beyond just allosteric inhibition of this channel, and we need to understand these channels not just as static proteins in the membrane, but actual proteins that move in and out of the membrane.”
In the study, researchers found that scaffolding protein ankyrin-3 (Ank3) interacts with Nav1.8 to drive neuronal hyperexcitability and pain-triggering signals.
SLiPs are mimetics designed to “function as a bait molecule,” said Powell, who explained that the researchers wanted to test if Mimetic's SLiP was able to bind directly to Ank3, and outcompete its binding potential to its desired target, Nav1.8.
“The SLiP technology is very amenable to modifications as well as different targets,” Powell said. “We really do have confidence that we'll be able to go after many different channelopathies and that this SLiP technology can extend beyond ion channels—we just have to show it.”
Massachusetts biotech Mimetic was founded in 2023 with a mission to explore the therapeutic potential of SLiPs. The SLiP used in this study serves as “the prototype for a class of various SLiPs,” Powell noted.
“This molecule did lead to the development of multiple SLiP candidates that we are currently evaluating,” he added.
Common treatments for neuropathic pain include the gabapentinoid pregabalin and the serotonin-norepinephrine reuptake inhibitor duloxetine. Vertex Pharmaceuticals already has an allosteric Nav1.8 inhibitor for acute pain on the market in the form of the non-opioid analgesic Journavx, but the biopharma has yet to secure approval for the drug to treat peripheral neuropathic pain.
Another hot area of research into treating nerve pain is psychedelics, with a group from MD Anderson Cancer Center recently reporting the success of the magic mushroom extract psilocybin in reducing chemotherapy-induced peripheral neuropathy.