Using human IPSC derived nociceptors as a cellular model to investigate and therapeutically target Nav1.7

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Chronic pain is a major health problem affecting 1 in 5 of the general population and unfortunately current treatments are inadequate. This is because they only work in a minority of patients and they are also associated with side effects. Moreover, a significant number of clinical trials testing new drugs to treat pain have failed, despite these drugs showing encouraging results in animal models. This may partly be due to differences in the structure and function of some of these drug targets between human and rodent species. We therefore need to understand more about the fundamental biology of pain processing in humans and find intermediate steps to test new drugs in a human cellular model. We will use human induced pluripotent stem cells (iPSCs) which are cells that have been taken from healthy volunteers (and in some cases patients) and reprogrammed so that they can be grown in the laboratory We can then use these cells to generate human nociceptors. Nociceptors are the sensory neurons which sense tissue injury giving rise to the sensation of pain. We will use these cells to investigate the role of and test drugs targeting the ion channel Nav1.7, which is an important target for developing new drugs to treat pain. Ion channels are important for regulating the excitability of neurons and this channel in particular is a key drug target because data from rodents suggest that it is needed for the generation of electrical signals in nociceptors. Nav1.7 shows selective expression within sensory neurons (so targeting this ion channel should avoid side effects in other regions of the body such as the heart and brain). Finally, patients with mutations in the gene encoding this ion channel are born unable to perceive pain. We will use gene technology so that we can produce a 'tagged' version of human Nav1.7 in order to determine how this protein is trafficked to the different specialised regions of human nociceptors. We will also determine which other proteins can bind to hNav1.7 and whether these proteins may modulate its function or alter its trafficking. We will determine whether the new drugs being developed to target hNav1.7 can alter the excitability of human nociceptors and whether this is mediated through effects on hNav1.7. Ultimately, we hope to learn more about the fundamental role of Nav1.7 and its interactors in regulating the excitability of human nociceptors and validate human iPSC derived nociceptors as a platform for drug discovery.