Human stem cell models for neuroscience drug discovery
Zameel Cader is the academic lead for the StemBANCC consortium, funded by the Innovative Medicines Initiative (IMI). This large group of academic institutions across Europe and large pharma partners has developed a biorepository of induced pluripotent stem cell lines from several hundred subjects. These are now available for research use [EBiSC catalogue page].
Our group leads on the development of novel human cellular models from trigeminal ganglion pain sensory neurons and dorsal root ganglion pain sensory neurons in order to better understand pain disorders such as migraine. This includes developing iPSC lines from patients with mutations that cause migraine and neuropathic pain, and then measuring the excitability and synaptic activity of pain sensory neurons. We can then use these models to screen for new drugs that may have therapeutic value in pain.
We have also been establishing new methods to generate blood-brain-barrier capillary endothelial cells from iPSC. The role of the neuro-vasculature in brain disorders has been relatively neglected but with our new cellular models, we can now examine how brain endothelial cells, pericytes and arterial smooth muscle interact with neurons and glia. Our human blood-brain-barrier model can also be used to investigate whether newly developed drugs and antibodies are likely to cross into the brain. Learn more about licensing this technology.
TRESK as a Key Regulator in Pain
We previously reported in a large family with migraine, a frameshift mutation in the gene KCNK18, which encodes a tandem-pore background potassium channel, TRESK. This ion channel is expressed in pain salient regions such as the trigeminal ganglion and dorsal root ganglion. We believe that loss of TRESK function increases cell excitability and responsiveness and thereby lowers the threshold for pain. We are now exploring genetic modifiers in primary cell culture and human iPSC pain models. We have an active drug discovery programme to identify small molecules that modulate TRESK.
The Role of Cannabinoids in Pain
Using our unique human iPSC pain models, we will investigate how exogenous cannabinoids affect the molecular profile (transcriptome) of cells involved in pain disorders. The overall aim is to identify specific components in cannabis plant extract that could be used to treat pain. This work is part of a broader programme of research in Oxford on exogenous cannabinoid biology [KCP funding announcement].
Researchers: To be recruited
Human Centric Drug Discovery
We are investigating the integration of clinical informatics, molecular informatics and human cellular assays in order to identify currently approved and safe drugs that may have therapeutic efficacy for new disease indications. This approach to drug re-purposing and target discovery may provide a rapid and cost-effective way to get better treatments for patients. The research is funded by Oxford Science Innovations, with additional support from the NIHR Oxford BRC.