Osteoarthritis is a chronic disease of the articulating joints, hallmarked by cartilage degradation.  Ten percent of the UK adult population have symptomatic, clinically diagnosed osteoarthritis, yet current treatments are limited to pain relief, physical therapy, and surgical replacement of affected joints. The development of disease-modifying osteoarthritis drugs (DMOADs) would revolutionise the field.

The expression of transcription factors (TFs) becomes dysregulated in the articular cartilage of osteoarthritis patients, with levels of catabolic TFs rising, and negatively impacting trans-regulatory networks within chondrocytes. Consequently, TFs are extremely attractive therapeutic targets yet, due to a lack of ligand binding sites, they have long been considered undruggable.

A novel class of drugs, PROteolysis TArgeting Chimeras (PROTACs) are generating enormous excitement amongst the pharmaceutical industry, and currently comprise 30% of all pipeline drugs. PROTACs target specific proteins for proteasomal degradation, circumventing many traditional barriers to drug development. Recently, TRAnscription Factor TArgetting Chimeras (TRAFTACs) have been reported, which target and degrade DNA-binding proteins. TRAFTACs have never been tested for efficacy in musculoskeletal disease.

In this Scholarship, the student will apply this cutting-edge TRAFTAC technology to degrade catabolic TFs in human chondrocytes using a series of complementary aims:

1. Engineer TRAFTACs to degrade the prioritised TFs and optimise their use in the chondrocyte cell line Tc28a2.
2. Test TRAFTACs in chondrocytes differentiated from adipose-derived stem cells and measure the phenotypic, transcriptomic, and proteomic response.
3. Develop a proteomic assay to determine the health status of primary human chondrocytes and use this to measure the impact of TRAFTACs upon the cells.

The overarching aim of this multidisciplinary research is to provide proof-of-concept for PROTACs as novel therapeutics in musculoskeletal disease, with a long-term goal of translating our research. The future development of DMOADs would benefit millions of older people in the UK, allowing them to live independent, pain-free lives.