Harnessing the splicing code for targeted control of gene expression
Alternative splicing of messenger RNA precursors plays important roles in tissue-specific gene regulation and biological regulatory mechanisms, where it can radically 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 AS specificity is lacking. This gap in basic knowledge limits future opportunities to harness splicing modulators as tools to study gene function, novel therapeutics or other biotech applications. The UNLEASH Project addresses head-on major technical challenges that have limited progress in the alternative splicing field. Building on extensive preliminary data, we will use a multidisciplinary approach that combines chemical, structural, cellular, systems biology and computational methods to characterize mechanisms of splice site selection and identify targets for tool compounds that will modulate these mechanisms. The outcomes will define key regulatory sequences, splicing factors and molecular interactions involved, thereby illuminating how the splicing machinery efficiently accommodates, yet also discriminates between, a wide range of splice site sequences. Our primary goal is to answer the central question, ‘Is it possible to modulate splicing with high specificity using small molecules?’ Success will transform our basic understanding of human gene expression and unleash major opportunities for Pharma to develop new therapeutics harnessing modulation of splice site selection. In summary, we expect the impact of this project to be a step-change advance in our mechanistic understanding of pre-mRNA splicing and how this can be regulated and harnessed for future therapeutic and biotechnological applications by controlling protein expression.
