Na v 1.7 target modulation and efficacy can be measured in nonhuman primate assays

Autor: Richard L. Kraus, Ronald M. Kim, Jeanine E. Ballard, Thomas J. Greshock, Andrea K. Houghton, Michelle K. Clements, Marie A. Holahan, Andrew Danziger, Christopher S. Burgey, Yuxing Li, Mark E. Layton, Jordi Serra, Parul S. Pall, Rebecca M. Klein, Joshua D. Vardigan, Dan Zhou, Fuqiang Zhao, Christopher Daley, Darrell A. Henze
Rok vydání: 2021
Předmět:
Zdroj: Science Translational Medicine. 13
ISSN: 1946-6242
1946-6234
Popis: Humans with loss-of-function mutations in the Nav1.7 channel gene (SCN9A) show profound insensitivity to pain, whereas those with gain-of-function mutations can have inherited pain syndromes. Therefore, inhibition of the Nav1.7 channel with a small molecule has been considered a promising approach for the treatment of various human pain conditions. To date, clinical studies conducted using selective Nav1.7 inhibitors have not provided analgesic efficacy sufficient to warrant further investment. Clinical studies to date used multiples of in vitro IC50 values derived from electrophysiological studies to calculate anticipated human doses. To increase the chance of clinical success, we developed rhesus macaque models of action potential propagation, nociception, and olfaction, to measure Nav1.7 target modulation in vivo. The potent and selective Nav1.7 inhibitors SSCI-1 and SSCI-2 dose-dependently blocked C-fiber nociceptor conduction in microneurography studies and inhibited withdrawal responses to noxious heat in rhesus monkeys. Pharmacological Nav1.7 inhibition also reduced odor-induced activation of the olfactory bulb (OB), measured by functional magnetic resonance imaging (fMRI) studies consistent with the anosmia reported in Nav1.7 loss-of-function patients. These data demonstrate that it is possible to measure Nav1.7 target modulation in rhesus macaques and determine the plasma concentration required to produce a predetermined level of inhibition. The calculated plasma concentration for preclinical efficacy could be used to guide human efficacious exposure estimates. Given the translatable nature of the assays used, it is anticipated that they can be also used in phase 1 clinical studies to measure target modulation and aid in the interpretation of phase 1 clinical data.
Databáze: OpenAIRE
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