Following the Scottish Research and Drug Development Forum meeting, DDW’s Diana Spencer provides a snapshot of drug discovery in Scotland.
With over 150 pharma services/supply companies and 19 universities, Scotland is one of the most advanced life science sectors in the UK and the world. To demonstrate how Scotland is continuing to innovate and shape drug discovery, on April 27, 2023, ELRIG UK hosted the Scottish Research and Drug Development Forum at the Beatson Institute for Cancer Research in Glasgow.
The event brought together organisations representing different aspects of drug discovery, including research institutes, academia and industry, emphasising the importance of partnership and collaboration in this dynamic sector.
The role of animal models in drug discovery following the FDA’s Modernisation Act was a theme that ran through the day, as many presentations looked at alternative model systems and addressed how we can reduce, reuse and recycle this type of research.
Introduction to the CRUK Beatson Institute
The first speaker was Professor Owen Sansom, Director of the Cancer Research UK Beatson Institute, who gave two presentations.
Established in 1912, the Beatson Institute has close ties to the University of Glasgow’s clinical cancer research groups. As one of four Cancer Research UK institutes, it was a founding member of Cancer Research Horizons. The aim of the researchers is to understand the mechanisms that regulate cancer cell proliferation, survival and dissemination; to identify critical components of these pathways as targets for novel cancer therapies; and to help translate this knowledge to patient benefit.
The focus of the Beatson’s research is on areas of pressing need in Scotland, such as colorectal, hepatocellular, pancreatic and mesothelioma cancers.
Addressing diseases of unmet need through high content phenotypic screening
The second presentation was given by Neil Carragher, Professor of Drug Discovery and Director of Translation at the University of Edinburgh, who discussed the benefits of high content phenotypic screening.
Although target directed drug discovery is the most common approach, it is slow and expensive and has high attrition rates. Phenotyping, in contrast, can produce a hit/lead without a target.
The university had applied this approach to oesophageal adenocarcinoma (OAC), using cell painting to find compounds that target the cancer cells. They screened 20,000 compounds across eight cell lines. Four new chemical hit clusters were identified with an indicative structure-activity relationship, which resulted in one novel OAC target.
There are various other phenomics projects currently ongoing. One is investigating compounds to treat multiple sclerosis in collaboration with the Siddharthan Chandran Centre for Clinical Brain Sciences, which resulted in the spin-out company Pheno Therapeutics. The National Phenotypic Screening Centre, Cancer Research UK and Janssen are working together on a glioblastoma project, while UCB Pharma is collaborating on a study into inflammatory fibrosis, which is being partially funded by LifeArc.
Human iPSCs for better human disease models
Next, Mhairi Rodgers, Site Lead at Axol Bioscience, advocated the use of induced pluripotent stem cells (iPSC) human disease models to expand scientific knowledge and de-risk drug development.
The company uses donated cells from patients and iPSC technology to build physiologically relevant in vitro models, with a special focus on neurodegenerative diseases like Alzheimer’s disease.
Rodgers said that the FDA Modernisation Act had encouraged a reduction in animal testing and opened up new opportunities, allowing human disease models technology to advance at a faster rate.
Using complex models of cancer for preclinical testing
After a coffee break, Prof Sansom was back behind the podium talking about the MRC National Mouse Genetics Network. The Network aims to integrate mouse genetics, cell and tissue systems and deep phenotyping with human data, and develop preclinical platforms that facilitate the rapid translation of mouse data into the clinic. It also hopes to optimise production, archiving and sharing of mouse model data, following the principles of the three Rs: reduce, reuse, recycle. While the hub of the Network is the at the Mary Lyon Centre in Oxfordshire, it works with collaborative disease clusters around the UK.
Prof Sansom said: “A lack of models were previously holding back progress in colorectal cancer, but there has been a paradigm shift in the last five years in terms of models and we can now achieve exciting interventions by combining the use of different models.”
Advances like genetically engineered mouse models (GEMMs), patient-derived xenografts (PDXs) and organoids are allowing the integration of mouse models with human cohorts.
He also pointed out that in precision oncology, the host is going to be a very important factor to consider, in terms of age, but also BMI and other factors.
Bioengineering 3D adipose organoids for type 2 diabetes drug discovery
Elaine Duncan, PhD Student at the University of Glasgow, shared her research and the challenges of developing a functional assay for spheroids.
Research has shown that metabolism + inflammation leads to insulin resistance in type 2 diabetes. 2D cell culture models don’t show enough complexity to analyse this link, while animal models are high cost and raise ethical concerns. 3D spheroid and organoid models are of human origin and are bridging this gap, so Duncan is currently working to create an insulin resistant organoid, which has a biosensor to give a real-time read-out function, and will ultimately support the discovery of new treatments.
The development of a 3D functional assay has been challenging due to a lack of validated assay formats. However, she has identified FFA4, a G protein-coupled receptor (GCPR) with the therapeutic potential to improve insulin sensitivity in metabolic disorders. The research has shown that incorporating a genetically encoded biosensor into a spheroid model may allow real-time measurement of function and an opportunity for drug screening.
Combining skills, expertise, and facilities to respond to high consequence viruses at CVR-CRUSH Drug-Screening and Resistance Hub
The day’s final presentation was from Agnieszka Szemiel, Facility Manager at the University of Glasgow, who discussed CRUSH, part of the Centre for Virus Research (CVR) based at University of Glasgow. Established in partnership with LifeArc, CRUSH strives to address pandemic preparedness, covering SARS-Cov2 and other high consequence viruses.
CRUSH provides engineered viruses for vaccine development, but also takes initial in vitro screening of antiviral compounds through to functional studies and on to pre-clinical animal models for efficacy evaluation of promising candidates. The facility can provide preclinical animal models, high and medium throughput screening, validation assays, kinetic assays, drug-resistant assays and drug combinations.
In response to a question regarding the best way to treat viruses, Szemiel said that while vaccines are good, an antiviral pill would provide easier access to treatment in the event of a pandemic, though such antivirals are currently only given in hospital.
A thriving centre of research
There were also fascinating talks on ‘New degrading mechanisms to move beyond PROTACs’ from Wojciech Stec, Principle Scientist at Amphista Therapeutics and ‘Production of monoclonal antibodies using a phage-display scFv library: cheaper, faster, and more flexible than hybridoma strategies’ from Jack Brydon at The Antibody Company.
It was a lively meeting, with lots of discussion and opportunities for networking. As a whole, the event emphasised the breadth of preclinical research taking place in central Scotland at the moment, the level of expertise available in the region and the vital importance of bringing this expertise together in collaborative projects between charitable organisations, industry and academia.
