Revealing mechanism and functionality of repurposed compounds in ageing research – new role for Bisphosphonates

Overview 

A multicentre drug repurposing pipeline and collaborative team (including above) established through seed-funding from the Oxford-led UKSPINE Ageing Network (Research England) and utilising treated human patient samples, cellular screening assays and multiplex proteomics, has confirmed new potential for the well-established bisphosphonate (BP) class of drug. BPs have represented the frontline treatment for disorders of excessive bone loss for decades, are accessible, affordable, and well-tolerated. Recent clinical studies indicate significant beneficial extra-skeletal effects following BP treatment (28% reduction in all-cause mortality, 67% reduction in cardiovascular mortality, 39% reduction in deaths from cancer, 24% reduction in respiratory disorders, 59% reduction in ICU mortality) however, the cell types and intracellular mechanisms mediating these effects remain unknown.

This project will examine the scientific basis for repurposing BPs as potential gero-protective agents, reveal mechanism through which BPs might function in non-skeletal cell types and highlight new pathways which might be targeted by BP analogs

Building upon existing screening techniques where cell/tissue types and specific clinically-utilised and novel BPs and have been prioritised for further investigation, this project will determine i) how BPs (ZOL, ALN, CLO, OX-14) increase cell proliferation and protect against ageing-linked challenges (oxidative stress, onset of senescence) in cardiomyoblasts, hepatocytes and macrophages in vitro. New targets for BP action are explored by Cellular Thermal Shift Assay with unknown proteins identified using mass spectrophotometry, and cellular validation confirmed in human cell types using standard pharmacological and molecular manipulation. Data sets will be probed alongside our existing BP-treated patient secretome profiles; ii) local effects of BP treatment in old/young mice will be analysed using spatial transcriptomics (as developed at MDC) to determine senescence and ageing-linked tissue changes over time, confirm a protective impact of BPs and reveal and/or confirm involvement of new targets.

Role of the commercial partner

The Medicines Discovery Catapult (MDC) is an independent, not-for-profit Research Technology Organisation focused upon drug target development and acceleration toward clinical use, including multiple model systems for drug discovery and testing, such as that proposed in this project (e.g. transcriptomic/proteomic analysis, single cell gene expression analysis, mass spectroscopy, histology and cell culture).

The MDC supervisor team comprises experts with decades of experience across large pharma, academia, leading technology providers, SMEs, charities and start-ups, offering experience of every stage of drug discovery, including biomarker analysis, cell model analysis/validation, target & pathway engagement, drug delivery & biodistribution, informatics and patient/public interface. 

Training and support available

Our dept (NDORMS) has a dedicated training programme for D,Phil students including technical, ethical sessions, and clear indications of support networks within NDORMS and across MSD. Direct supervision is provided by primary supervisor and immediate research group, alongside supporting supervisors and thesis committee. This includes use of new techniques (e.g. CETSA including mass spec processing) and bioinformatic analysis.

Training and support will also be provided by MDC in the use of any new techniques, along with skills outside the laboratory including the grant application process, assembly of journal papers and presentation of data to a scientific and lay audience.