MICA: An iPSC based screen for candidate pain modulating compounds

Chronic pain is a global health problem which affects approximately 30% of all adults. Current therapies have limitations in their effectiveness or side effects therefore there is an urgent need to develop more precise and effective forms of medication for individual pain causing conditions. The search for new drugs has been hampered by the lack of methods to translate early identification of promising molecules into clinically effective treatments - for example, to date much of the research needed to show drug effectiveness has been carried out in animal models which don't always show the same pain response as humans. We will address this problem by establishing and validating a laboratory model of pain causing mechanisms that was developed by Pfizer before its withdrawal from the pain treatment market and the UK as a whole. This model was developed by one of the other co-applicants on this proposal (James Bilsland) and uses nerve cells made from induced pluripotent stem cells that were themselves generated from patients who suffer from a rare but debilitating pain condition called erythromelalgia. The nerve cells that detect pain in these patients are hypersensitive - that is they produce signals that the brain interprets as pain much more easily than those of normal people. We call this phenomenon "hyperexcitability" and our aim is to identify chemical compounds which can reduce the rate ease with which erythromelalgia derived nerve cells can produce pain signals. Naturally this would be extremely valuable for erythromelalgia patients but identifying compounds to stop hyperexcitability could be much more important since there is a lot of evidence that this phenomenon contributes significantly to a lot of other pain causing conditions. In short, if we find pain killing drugs using our proposed method, they are likely to be effective against pain of many types.

The global objective of this proposal is to establish, validate and apply an assay system for the identification of novel pain therapies. The market for pain management drugs is expected to reach $41.5 billion in 2017. Moreover, in the light of an ageing population, this is set to increase still further so the unmet need of pain therapy is great indeed. The need exists because current pain therapies are either incompletely effective or have undesirable side effects. Our proposal is to test an induced pluripotent stem cell based assay to identify new therapeutics to treat neuropathic and chronic pain. The assay we will use is an innovative approach using human patient derived cells with defined monogenic mutations that cause in-vitro sensory neurons to display hyper-excitability in patients with erythromelalgia. The assay has been validated to industrial standards and represents the only iPSC based model of this type to date. By combining the expertise of Newcastle University in generation of iPSC derived sensory neurons and multielectrode array based electrophysiological analysis with the drug development and clinical neurophysiology of University College London and partnerships with large pharma companies we will apply this technology in the context of a collaborative drug discovery programme to identify new candidates in a phenotypic screening approach. In short, we will apply sensory neurons made from erythromelalgia patient specific iPSC to multi-electrode arrays and monitor the effects of small molecules from a chemogenomic compound library on the hyperexcitable action potential of the diseased sensory neurons. This improves the state of the art in pain drug discovery since it uses cells that are closer to the functional physiology of human sensory neurons.

We anticipate that the establishment and validation of the hyperexcitability based assay system will allow us to undertake high throughput screening of small molecule compound libraries with the aim of finding new potential treatments for pain. A successful outcome (e.g. identification of prospective pain modulating compounds) to the project as a whole will potentially have a very large impact on society, since treatment of chronic pain is currently a large and unmet need. In view of this the application of an induced pluripotent stem cell model of erythromelalgia will be a powerful exploratory technique in the search for new pain medicines. The multi-electrode array system needed for this investigation can be applied to analysing the electrophysiological response on many types of electrically active cells ranging from various types of neurons, through cardiomyocytes and cochlear hair cells to retinal cell types such as photoreceptors and the retinal ganglion cells. A successful outcome to this funding application will enable our combined academic groups to search for novel therapies not only for chronic pain, but also for diseases of the sensory epithelia (e.g. age related deafness, age related macular degeneration) whilst retaining the capacity to analyse toxicity / side effects upon other organ systems such as the heart. The potential impact of successful drug discovery programmes in these areas is enormous; the market for new pain therapies is very large indeed and those of hearing/visual problems are similarly significant thus the potential contribution of novel therapies for any of these conditions on the success of the UK pharmaceutical industry is highly desirable.