Droplet-based Microfluidic Platform for Intracellular Ion Channel Drug Discovery

Ion channels are proteins that are involved in the regulation of almost every cellular mechanism and they constitute the second largest class of pharmacological drug targets. A family of these channels are located in the inner compartments of a cell (i.e. they are intracellular) and they are typically excluded from industrial large-throughput automated screening (e.g. automated patch clamp technology) that probe ion channels only in the outer cell membrane. As such, implications arise that affect the hit discovery rate of new drugs for such proteins. This proposal aims to produce and test a new microsystem technology for drug screening of human intracellular ion channels. The system will comprise a medium-throughput microfluidic prototype relying entirely on synthetic cell membranes harbouring intracellular ion channels. Whilst developing this new technology, this study will investigate two proteins that are involved in cancer and neurodegeneration, namely CLIC1 (used for validation) and CLIC4, which currently has no known pharmacological identified drug. Drug screening will be done in collaboration with industrial partners AstraZeneca and Smartox.

New technology is widening the chance of developing new pharmacological compounds and has the potential to create new jobs and have economic and societal impact on healthcare.
Economic impact: The average expenditure to develop and bring to market a new drug is estimated to be approximately $2 billion, with target identification, discovery and the development of a new chemical compound before clinical trials accounting for 30% of the total cost. Commercialization of the developed platform has potential to add considerable information over the gold standard obtained by current electrophysiological tests with automated patch-clamp technology and impact the pre-screening stages of compounds, most of which is currently provided as a service by CROs and/or CMOs. Therefore, outcomes from this project have potential to carve a unique sector in the market of drug screening instrumentation. To assess this impact and available opportunities, we have secured the participation of members from academia, healthcare technology and industry to act as an advisory board for consultancy regarding knowledge transfer and commercialisation.
Industrial impact: The developed system will be tested in collaboration with project partner AstraZeneca for the development of pharmacological assays based on combinatorial chemistry approaches. Outside the immediate benefit in identifying new active compounds for the CLIC4 channel, the potential for translating the developed procedures for other pharmacologically relevant eukaryotic ion channels present cost-saving arguments against current live-cell based, large-screening assay in the Pharmaceutical industry. In addition, the collaboration with project partner Smartox will explore a further application of the technology for use with limited resources of venom samples only available in extremely small quantities that currently elude industrial automated screening. The proposed technology has the potential to greatly impact drug discovery by identifying new efficient venom-derived drugs. Together, this double partnership will enable us to address different screening needs for both SME and the Pharmaceutical Industry.
Societal impact: Identification of new drug candidates from the developed technology will expand the panel of drugs with implications in cancer, mitochondrial dysfunction and neurodegenerative diseases. Improving the efficacy of identified drugs at preclinical level is expected to improve outcomes during clinical trials. Therefore, wide societal benefits would be in the form of new medicine and their improved efficacy. Furthermore, the applicability of the proposed technology to the other identified applications (see academic beneficiaries) and healthcare related fields could impact the screening of vaccines and environmental toxins, all of which will produce massive societal benefits.