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Research conducted at the University of Bristol since the late 1990s has pioneered the development of over 60 chemical probes that are selective for individual ionotropic and metabotropic glutamate receptors. The development of these probes has led to numerous commercial impacts, including: the establishment of two companies, which both sold during the assessment period for a combined value of £85 million, and sales revenue for global providers of biochemicals. This research has also stimulated considerable industry investment in drug development.
Research by the School of Pharmacy has underpinned the development of fluorescent ligand probes that have opened-up new pathways in drug discovery. These ligands have been commercialised through the formation of the spin-out company CellAura Technologies Ltd, and have been made globally available through a number of distributer agreements. Customers include pharmaceutical companies (e.g. Pfizer, AstraZeneca), drug discovery biotechs (e.g. Addex, Heptares) and drug discovery technology providers (e.g. CisBio). These ligands provide alternatives to the use of radio-ligands, giving more informative and safer solutions for industrial drug discovery. This has, for example, enabled: a new direction in G protein-coupled receptor research at Novartis Pharmaceuticals UK Ltd; validation of Promega Corporation's new drug-binding assay; and superior performance in the establishment of cell lines at inSCREENex GmbH.
Original basic research on melatonin receptors undertaken at the Rowett Institute, University of Aberdeen, and funded by the Scottish Government, provided the opportunity for Servier pharmaceuticals to develop a new line of therapeutics for depression.
The company exploited Rowett know-how and invested in new research to develop a new line of compounds and to understand their structure-function relationships. This work enabled the development of melatonin analogues for clinical trials and ultimately led to the development of melatonin compounds for treatment of circadian related disorders.
One (S20098) was identified as having positive effects for disrupted circadian rhythms and beneficial outcomes for patients with depression. S20098 (also known as Agomelatine) was launched after EU authorization in 2009 as a novel anti-depressant drug called Valdoxan®. Today Valdoxan is an award winning anti-depressant drug recognised for its novel mechanism of action and few side effects. Valdoxan is the only anti-depressant drug to be brought to the market in the last 10 years. In summary, supported by investment from industry research undertaken at the University of Aberdeen contributed to the development of a novel antidepressant drug that provides a new clinical intervention with advantages over previously available antidepressants that will make a significant impact on the health and well-being of those afflicted by depression.
Professor Geoffrey Burnstock and colleagues' establishment of the molecular structure of the P2Y class of receptor led to the cloning of several receptors within this class, which are increasingly seen as therapeutic targets for a variety of disorders. Indeed, drugs acting at these receptors are already improving patient health worldwide by reducing the risk of thrombotic events in people suffering from myocardial infarction or ischaemic stroke (via P2Y12 receptor antagonists) and by relieving the symptoms of dry eye disorder (via P2Y2 receptor agonists). Burnstock and colleagues also cloned the P2X3 receptor which mediates pain information, and P2X3 antagonists are being developed as novel analgesics. As well as clear clinical benefits, these drug developments are associated with substantial economic and commercial benefits.
Fluorescent ligand technologies developed by Professor Hill and Dr Briddon in the Pharmacology research group, in collaboration with Professor Kellam in the School of Pharmacy, permitted biophysical analysis of G-protein coupled receptors (GPCRs) at the individual cell and molecule level for the first time. The technologies have been commercialised through the spin-out business, CellAura Technologies (and their distributors Abcam, Sigma-Aldrich and others), generating revenues and making the products available to researchers and drug discovery communities worldwide. Custom product developments with global pharmaceutical companies and drug screening reagent providers have generated further partnership revenues and technology benefits. Nottingham-trained researchers are now employed worldwide, broadening the technology's impacts.
Members of the Pharmacology Research Group identified hitherto unknown properties of G protein Coupled Receptors (GPCRs): that ligands can signal differentially through both G-protein-coupled and β-arrestin pathways. This led to the concept of GPCR `biased signalling' and development of fluorescent reporters to quantify β-arrestin signalling. These discoveries have been adopted widely by the pharmaceutical industry, attracting R&D investment and collaborative research funding, to drive discovery of new drugs operating through `biased signalling'. The commercial opportunity has also been exploited by screening reagent providers and contract screening organisations. These discoveries will ultimately produce better drugs to treat GPCR-based diseases to improve human health.
In June 2013 Arena launched Belviq® (generic name: lorcaserin) as a novel drug treatment for obesity. Lorcaserin was approved by the Federal Drugs Administration (FDA — the USA drug regulatory body) on 26 June 2012 and scheduled by the Drug Enforcement Agency (DEA) in April 2013. The scientific rationale for the development programme for lorcaserin, which is a serotonin 2C receptor agonist, as a treatment for obesity rested, in significant part, on research carried out between 1997 and 2010 at the University of Sussex.
Research by Professor Kevin Fone in the Neuroscience group has established and characterised rodent models of CNS disorders that have been instrumental in validating several 5-hydroxytryptamine (5-HT) receptors as therapeutic drug targets to treat learning and memory dysfunction in humans. Specifically, animal studies to validate the 5-HT6 receptor for cognitive impairment in Alzheimer's disease (AD), depression and schizophrenia have resulted in R&D investment in drug discovery programmes by several global pharmaceutical companies. Consequent advances in healthcare benefits (current and potential) are also summarised.
Research at the University of Sheffield contributed to the development by GlaxoSmithKline (GSK) of a drug to treat Irritable Bowel Syndrome (IBS) that has transformed the lives of thousands of patients and generated significant revenue. The drug, alosetron, which blocks 5-HT3 receptors in the gastrointestinal tract, was approved by the Food and Drug Administration (US) (FDA) in 2000 and launched under the trade name Lotronex. It is currently the only drug on the market aimed specifically at the treatment of diarrheal IBS. Although GSK voluntarily withdrew the drug from the market following concerns over possible side effects, Lotronex was relaunched in 2004 following petition from IBS sufferers and user groups. The licence for Lotronex was sold in 2008 to Prometheus Laboratories, Inc. and annual sales of the drug now exceed $34 million. In 2011 Prometheus was bought by Nestle for an estimated $1.1billion. This case study has significant impact on commerce and health and welfare.
The work of Colledge and colleagues between 2000 and 2007 has identified and characterised a molecule which is an important regulator of fertility: the neuropeptide kisspeptin.
The identification of its role in fertility has led to kisspeptin and its analogues being tested in clinical trials to make IVF treatment safer (Phase II: one trial), and as therapeutic agents for reproductive system conditions such as delayed puberty, menopause and absence of menstruation (Phase I: four trials). In April 2013, 11 months after the start of the Phase II IVF study, a healthy baby has been born to a participant treated with kisspeptin. Patients enrolled in these fertility trials have testified to the improvement in quality of life which the hope of being able to conceive that this alternative to conventional IVF has brought them.