A Review of the Therapeutic Targeting of SCN9A and Nav1.7 for Pain Relief in Current Human Clinical Trials

Abstract

Introduction There is a great need to find alternative treatments for chronic pain which have become a healthcare problem. We discuss current therapeutic targeting Nav1.7. Areas Covered Nav1.7 is a sodium ion channel protein that is associated with several human pain genetic syndromes. It has been found that mutations associated with Nav1.7 lead to the loss of the ability to perceive pain in individuals that are otherwise normal. Several therapeutic interventions are presently undergoing preclinical and research using the methodology of damping Nav1.7 expressions as a methodology to decrease the sensation of pain leading to analgesia. Expert Opinion It is our strong belief that there is a viable future in the targeting of protein of Nav1.7 for the relief of chronic pain in humans. The review will look at the genomics associated with SCN1A and proteomic of Nav1.7 as a foundation to explain the mechanism of the therapeutic interventions targeting Nav1.7, the human disease that are associated with Nav1.7, and the current development of treatment for chronic pain whether in preclinical or clinical trials targeting Nav1.7 expressions. The development of therapeutic antagonists targeting Nav1.7 could be a viable alternative to the current treatments which have led to the opioid crisis. Therefore, Nav1.7 targeted treatment has a major clinical significance that will have positive consequences as it relates to chronic pain interventions.

Therapeutic targeting of voltage-gated sodium channel NaV1.7 for cancer metastasis

“…Among the nine VGSC subtypes, Na V 1.7 ( SCN9A encoded gene) has been identified as a remarkable drug target for pain therapy ( Dormer et al, 2023 ). Na V 1.7 is predominantly expressed in peripheral nervous system (PNS) especially in all types of dorsal root ganglion (DRG) neurons ( William et al, 2005 ; Hameed, 2019 ) which have an important role in operating nociceptive signaling for pain and has been reported to be associated with inherited pain disorders ( Dib-Hajj et al, 2010 ; Ahuja et al, 2015 ; Dormer et al, 2023 ).…”

“…Among the nine VGSC subtypes, Na V 1.7 ( SCN9A encoded gene) has been identified as a remarkable drug target for pain therapy ( Dormer et al, 2023 ). Na V 1.7 is predominantly expressed in peripheral nervous system (PNS) especially in all types of dorsal root ganglion (DRG) neurons ( William et al, 2005 ; Hameed, 2019 ) which have an important role in operating nociceptive signaling for pain and has been reported to be associated with inherited pain disorders ( Dib-Hajj et al, 2010 ; Ahuja et al, 2015 ; Dormer et al, 2023 ). The mutations that upregulate the function of Na V 1.7 cause severe neuropathic pain such as inherited erythromelalgia, and paroxysmal extreme pain disorder ( Dormer et al, 2023 ), whereas mutations that cause loss of Na V 1.7 function result in congenital indifference to pain (CIP) ( Goldberg et al, 2007 ; Dib-Hajj et al, 2013 ).…”

Action potentials in postganglionic sympathetic nerves depend on NaV1.7

“…In humans, 10 homologous genes encode for the pore‐forming Na V channel α‐subunits, leading to functionally and pharmacologically distinct ion channels that differ with regard to their tissue distribution. The α‐subunit of Na V 1.7 is encoded by SCN9A , and this ion channel is present in peripheral nociceptive neurons (Dormer et al., 2023). Missense Na V 1.7 mutations reduce and gain‐of‐function Na V 1.7 mutations increase pain sensitivity in affected patients.…”

“…Missense Na V 1.7 mutations reduce and gain‐of‐function Na V 1.7 mutations increase pain sensitivity in affected patients. Based, in part, on such clinical observations, selective Na V 1.7 blockers have been developed as a potential new class of analgesics (Dormer et al., 2023). In addition to nociceptive neurons, sympathetic postganglionic neurons have long been known to express Na V 1.7 (Morinville et al., 2007).…”