Investigating the role of Leucine rich, glioma inactivated 1 (LGI1) in regulating pain sensitivity

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Trauma to the nervous system or diseases such as diabetes can injure neurons involved in signalling pain resulting in them becoming over-active and triggering the unpleasant sensation of pain. This type of pain, termed neuropathic pain, is unpleasant, long lasting and results in a poor quality of life for the sufferer. Neuropathic pain is common affecting between 5-10% of people and will become more common with an aging population. Although analgesics are available, this type of pain is particularly resistant to our current treatment strategies leaving the patient with few options. In addition, these drugs cause severe side-effects. This is of course hugely debilitating for the individual, negatively impacting on their way of life. Furthermore, it has significant economic ramifications (treatment costs, time spent off work) and in general is a burden on healthcare services which needs to be addressed. As a result, there is a pressing need to develop new better targeted therapies for the treatment of neuropathic pain. One obstacle has been the lack of translation from basic science findings into the clinic. Here I aim to address this by using patient samples to enhance the clinical relevance of my research findings. Autoantibodies targeting Leucine-rich glioma inactivate 1 (LGI1) are associate with neuropathic pain in patients. This molecule interacts with potassium channels which are important for regulating the activity of neurons involved in signalling pain. I will use these antibodies to determine if disruption of LGI1 is the cause of pain in these patients and whether this protein is a common regulator of neuronal activity and therefore a viable target for the treatment of neuropathic pain as a whole. The aim of my research will be to first assess whether LGI1 impacts on pain sensation by using genetically altered mice which no longer express this protein and assessing their behaviour to sensory stimuli. Using these mice, I will measure the activity of their pain signalling neurons and determine if LGI1 impacts on this activity through its action on potassium channels. Through my collaborations I will obtain LGI1 autoantibodies (-Abs) from a number of patients with neuropathic pain. I will use these samples to develop an animal model in order to ascertain whether these antibodies are causal to the development of neuropathic pain. This study will not only shed light on the role of LGI1 in pain biology, but also autoantibodies as a mechanism to cause abnormal pain sensation in patients. I will use established animal models of nerve injury to better understand the role of LGI1 in the development of neuropathic pain. LGI1 is a secreted molecule and its presence increases/stabilises the activity of potassium channels (therefore decreasing the activity of pain signalling neurons). To test the therapeutic potential of modulating this system, I will create soluble LGI1 protein for use in animals to increase the availability of LGI1 to pain signalling neurons. Using preclinical models, I will test whether LGI1 treatment can reduce neuropathic pain behaviours in mice and therefore determine the analgesic potential of this approach.These findings will of course directly help neuropathic pain patients with LGI1-Abs, where treatments are already available to reduce antibody levels and could then be used specifically to treat pain. In the wider context, new treatments for neuropathic pain will have huge societal benefits and these findings can be applied to other persistent pain conditions.