Background

Development of new drugs is time-consuming and expensive. Every year, many new candidate compounds fail at various stages in the drug discovery pipeline despite significant financial investment. As a consequence, it is estimated that each new drug requires an average of 15 years development and £2 billion. Being able to accurately differentiate between ‘winning’ and ‘losing’ drug targets at the beginning of the pre-clinical pipeline would therefore significantly increase the chances of new drugs successfully reaching the market, and with much less investment along the way.

Technology Overview

This technology rapidly identifies winning and losing targets much earlier in the discovery pipeline, avoiding years developing candidate compounds, many of which will eventually fail after considerable financial investment. These screens are initially performed using fly cells and use an RNAi-based approach with a phenotypic readout. Identified targets are then immediately validated for efficacy and cytotoxicity in human cells, providing a model-specific filter that results in a high pre-clinical translation rate and a reduced number of subsequent tests performed on mammals.

University of Exeter researchers have already successfully applied this technology to repurpose three drugs to treat three different diseases. Two of those have been through pre-clinical testing in collaboration with expert partners and are now poised for clinical trials:

Palbociclib for clear cell Renal Cell Carcinoma (ccRCC)

Mizoribine for Tuberous Sclerosis Complex (TSC) / IMPDH inhibitors

This platform has since been further enhanced through the use of a method Exeter researchers have called Variable Dose Analysis (VDA). This approach results in a 12-fold increase in the signal-to-noise ratio and sensitivity of RNAi-based screens. The most recent iteration of this platform, however, builds on all of the above and forms Exeter’s proprietary, multidimensional and combinatorial screening platform that will allow for complex screens at a much greater scale. In principle, this will allow for up to a thousand-fold increase in throughput, enabling all genes in the genome to be tested in a single combinatorial screen

Benefits

Established & Validated Benefits:

Rapid identification of effective and reliable targets
Efficient filtering of model-specific targets leading to a high rate of successful translation to complex models
Reduced need for mammal testing
Established history of success through pre-clinical trials

Additional Anticipated Benefits in Development:

Increased screening throughput by an estimated 1,000-fold
Rapid and unbiased whole genome screening for combinatorial drug treatments
Effective prioritisation of ‘winning’ targets based on prediction of toxicity, resistance pathways, drug and disease mechanisms
Improved patient stratification

Applications

This technology was developed for cancer and neurodegenerative diseases (NDDs) which are easily modelled in flies, but aspects of the platform can be applied to other diseases.

In addition to its use in the pharmaceutical sector, the researchers believe this platform may have wider applications in:

Toxicology screening
Biological & chemical threat assessment
Ecological impact evaluation

Opportunity

The University of Exeter believes this multidimensional target screening approach may be particularly suited to drug discovery for human and animal health, the development of pesticides and cosmetics, and the identification of countermeasures for biological and chemical threats. The University of Exeter would welcome feedback on any challenges or unmet needs these sectors face and how this technology might help address them.

The University of Exeter believe there is an opportunity to commercialise the platform and would welcome discussions with potential development or commercial partners and end users interested in helping achieve this.

Next-Gen Genetic Screening for Rapid Biological Discovery

Patents

IP Status

Seeking