Targeted ubiquitination of Na_V1.8 reduces sensory neuronal excitability

Chronic pain and addiction are a significant global health challenge. Voltage-gated sodium channel Na_V1.8, 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_V1.8 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_V1.8 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_V1.8-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_V1.8 currents in rodent sensory neurons. We demonstrate that UbiquiNa_Vis selective for Na_V1.8 over other Na_Visoforms and other components of the sensory neuronal electrogenisome. We then show that UbiquiNa_Vnormalizes the distribution of Na_V1.8 protein to distal axons, and that UbiquiNa_Vnormalizes the neuronal hyperexcitability inin vitromodels 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_V1.8 channels for analgesia.