Targeted ubiquitination of Na _V 1.8 reduces sensory neuronal excitability

Chronic pain and addiction are a significant global health challenge. Voltage-gated sodium channel Na _V 1.8, a pivotal driver of pain signaling, is a clinically validated target for the development of novel, non-addictive pain therapeutics. Small molecule inhibitors against Na _V 1.8 have shown promise in acute pain indications, but large clinical effect sizes have not yet been demonstrated and efficacy in chronic pain indications are lacking. An alternative strategy to target Na _V 1.8 channels for analgesia is to reduce the number of channels that are present on nociceptor membranes. We generated a therapeutic heterobifunctional protein, named UbiquiNa _V , that contains a Na _V 1.8-selective binding module and the catalytic subunit of the NEDD4 E3 Ubiquitin ligase. We show that UbiquiNav significantly reduces channel expression in the plasma membrane and reduces Na _V 1.8 currents in rodent sensory neurons. We demonstrate that UbiquiNa _V is selective for Na _V 1.8 over other Na _V isoforms and other components of the sensory neuronal electrogenisome. We then show that UbiquiNa _V normalizes the distribution of Na _V 1.8 protein to distal axons, and that UbiquiNa _V normalizes the neuronal hyperexcitability in in vitro models of inflammatory and chemotherapy-induced neuropathic pain. Our results serve as a blueprint for the design of therapeutics that leverage the selective ubiquitination of Na _V 1.8 channels for analgesia.