Development of Nav1.7 Monoclonal Antibodies for Treating Pain

ABSTRACT Chronic pain is a significant medical problem, affecting over 50 million Americans and representing the largest cause of disability and disease burden globally. Current pain relief treatments rely heavily on opioid drugs, which are only partially effective and have a limited therapeutic window. Sustained use of opioids increases the probability of misuse and addiction, which has led to the current opioid epidemic. Development of efficacious, non-opioid analgesics could help mitigate this public health crisis and address a significant unmet medical need. The voltage-gated sodium ion channel Nav1.7 is one of the primary components involved in pain signal generation. Loss-of-function mutations in the gene encoding Nav1.7 (SCN9A) result in complete insensitivity to pain in humans. Conversely, gain-of-function mutations contribute to painful peripheral neuropathies. Small molecule inhibitors of Nav1.7, such as lidocaine, also validate the role of Nav1.7 in pain, but such molecules cannot be used systemically because they also non-specifically inhibit other sodium channels such as Nav1.5 (required for cardiac function). Despite the remarkable role of Nav1.7 in pain sensation, drugs that specifically block Nav1.7 have so far proven ineffective in clinical trials. Small molecule therapeutics lack channel subtype selectivity, and poor bioavailability has made effective dosing difficult in clinical trials. Monoclonal antibodies (MAbs) offer therapeutic advantages of improved specificity and bioavailability, but there are currently no good MAbs against Nav1.7. Inhibitory MAbs against ion channels such as Nav1.7 are extremely challenging to isolate because, unlike soluble proteins, ion channels form complex transmembrane structures, are toxic when overexpressed, and are difficult to purify away from their native lipid environment. Here we propose to develop Nav1.7 monoclonal antibodies for treating pain.PROJECT NARRATIVE This project will contribute to public health and the treatment of chronic pain through the development of therapeutic MAbs against Nav1.7. Lead Nav1.7 MAbs with confirmed specificity and efficacy will be further developed with the goal of entering preclinical studies. Chronic pain is a major health crisis, affecting andgt;50 million Americans each year and is the leading cause of disability globally. Novel treatments are desperately needed as current opioid based drugs are only partially effective and sustained use can lead to addiction. Numerous animal studies, the efficacy of lidocaine, as well as human gain and loss of function mutations, have validated Nav1.7 as a target for pain relief. Moreover, widespread expression of Nav1.7 on peripheral DRG neurons makes the receptor accessible for MAb treatment (MAbs will not need to cross the blood-brain barrier).