Novel peptide approach reduces chronic neuropathic pain in mice

Understanding and treating chronic neuropathic pain has remained challenging due to its complex nature. New research from the lab of Clifford Woolf, MB, BCh, PhD, at Boston Children's Hospital's FM Kirby Neurobiology Center describes a novel approach for reducing pain by disrupting interactions within pain-sensing nerve cells called nociceptors. The mechanisms of this new approach have been licensed to a local biotech company - led by a former Woolf lab postdoc - and are being used to inform the development of new therapeutics. 

Voltage-gated sodium channels (Na_V ) play important roles in the electrical signaling of cells. The Na_V 1.8 channel has been shown to play a role in triggering such electrical signals within nociceptor dorsal root ganglion neurons, which the brain then perceives as pain. Preclinical strategies to inhibit Na_V have been successful in reducing neuropathic pain but have yet to produce similar results in clinical settings.

New results published today in Cell Reports Medicine help explain why. Previous drug development strategies for targeting Na_V 1.8 focused on reducing the channel's ability to open properly. Researchers have now discovered that Na_V 1.8 activity in neurons relies on an interaction with a scaffolding protein called ankyrin-G (Ank3) to maintain the heightened electrical activity in pain-triggering neurons during pathological pain. They found that disrupting that interaction with a short lipidated peptide (SLiP) reduces the levels of Na_V 1.8 in the cell membrane, quieting hyperexcitable pain-triggering neurons, and reducing pain-like behaviors in mouse models, while sparing acute protective pain.

"Exploring neuropathic pain has led to a discovery that not only redefines our understanding of the mechanisms of clinical pain," said Woolf. "It also provides evidence that short lipidated peptides, or 'SLiPs,' have immense potential to treat pain and other diseases." 

Boston Children's has licensed the intellectual property arising from this work to Mimetic Medicines, a Boston-based biotechnology company developing novel therapeutics based on this mechanism. Mimetic Medicines has taken the original academic discovery forward by developing investigational long-acting SLiP candidates designed to disrupt the Nav1.8–Ank3 interaction systemically. Their goal is to produce a non-opioid treatment for chronic neuropathic pain that selectively suppresses pathological pain signaling rather than normal sensory function. Rasheen Powell, a former postdoc in the Woolf lab, is the Chief Scientific Officer of Mimetic Medicines.