The Unleash Project

Our Primary Mission in the Unleash Project is to learn how to predictably manipulate the splicing of human gene transcripts.

All organisms on earth use proteins molecules to control the complex chemical reactions necessary for life. Proteins generate energy and they also make up the structural fabric of cells and tissues. Humans have approximately 20,000 genes that carry the information that allows cells to make these many different types of proteins. However, a process known as ‘Alternative Splicing’ (AS) allows these 20,000 genes to generate a much larger repertoire of proteins, because the initial RNA transcripts copied from each gene can be processed to create different mRNA products that each code for a different type of protein.

The alternative splicing of RNA plays important roles in tissue-specific gene regulation and biological regulatory mechanisms, as it can radically (as well as more subtly) alter protein expression, cell phenotypes and physiological responses. Altered splicing also contributes to disease mechanisms, ranging from neurodegeneration to cancer. Drugs modulating AS have recently provided the first therapy for Spinal Muscular Atrophy, a common genetic disorder, illustrating the huge potential for treating many other diseases of unmet need, if only we understood the mechanisms controlling splice site selection and how to regulate them with small molecules. 

Unfortunately, despite decades of research, a comprehensive understanding of the mechanisms that control specificity of AS is lacking. This gap in basic knowledge stops us from developing splicing modulators as tools to study gene function, novel therapeutics or other biotech applications. Our collaborative ‘Unleash’ Project addresses head-on the major technical challenges that have limited progress in the AS field.

With funding provided by the European Research Council (ERC) and the UK Research Institute (UKRI), the multidisciplinary Unleash project brings together researchers from Barcelona, Munich and Dundee. We are using the complementary expertise across the research teams which combines chemical, structural, cellular and systems biology.  This, together with computational approaches and bioinformatics, are use to characterize mechanisms of splice site selection. Our aim is to define key regulatory sequences, splicing factors and molecular interactions that determine how the splicing machinery efficiently accommodates, yet also discriminate between, a wide range of splice site sequences. We are identifying small molecule tool compounds that can control which splice sites are used and therefore modulate which combinations of proteins are produced. The Unleash Project can enable future therapeutic applications harnessing splice site selection, opening up new approaches for treating diseases of current unmet need.