Abstract

Translation from the laboratory to the clinic is key to decision-making in early drug development, and is often a gating step to determine the progression of a molecule. Two translational models will be described, one for a Nav1.7 blocker designed for neuropathic pain, the second for a Kv3.1/3.2 modulator under development for schizophrenia.
Nav1.7 ion channels for pain indications are well supported by genetic evidence. Loss of function mutation of the SCN9A gene results in congenital insensitivity to pain, while a gain of function mutation is associated with chronic hyperalgesia, or primary erthyromelalgia. Data from five patients with inherited erythromelalgia, who consented to participate in a clinical trial, shows that evoked pain in response to heat stimuli can be attenuated in the presence of a selective Nav1.7 blocker.
Kv3 channels are expressed in the brain on parvalbumin-containing interneurons, which play an important role in higher cortical function. Kv3 activation ensures sustained high frequency rapid action potential firing can be achieved. Lower levels of Kv3 expression have been found in post-mortem brain tissue from patients with schizophrenia, and it is thought that by enhancing Kv3 activity in patients, cognitive function may be improved. Ketamine challenge is a translational model often used in the development of drugs for schizophrenia. Low dose ketamine disrupts cortical function, observed during fMRI as activation (increased bloodflow) in specific brain regions. Attenuation of ketamine-induced bloodflow change has been used successfully as a translational model in the early clinical assessment of a novel Kv3 modulator.