Harnessing the splicing code for targeted control of gene expression (UNLEASH)

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Alternative splicing (AS) of mRNA precursors plays important roles in tissue-specific gene regulation and biological regulatorymechanisms, as it can radically alter protein expression, cell phenotypes and physiological responses. Altered splicing also contributesto disease mechanisms, ranging from neurodegeneration to cancer. Drugs modulating AS have recently provided the first therapy forSpinal 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 islacking. This gap in basic knowledge prevents opportunities to harness splicing modulators as tools to study gene function, noveltherapeutics or other biotech applications. This Project addresses head-on the major technical challenges that have limited progressin the AS field. Building on extensive preliminary data, we will use a multidisciplinary approach that combines chemical, structural,cellular, systems biology and machine learning to characterize mechanisms of splice site selection and identify targets for modulatingthese mechanisms using tool compounds. The outcomes will define key regulatory sequences, splicing factors and molecularinteractions involved, thereby illuminating how the splicing machinery efficiently accommodates, yet also discriminates between, awide range of splice site sequences. This will enable future applications harnessing splice site selection. Our primary goal is to answerthe central question, 'Is it generally possible to modulate splicing with high specificity using small molecules?' Success will transformour basic understanding of human gene expression and unleash major opportunities for Pharma to develop new therapeutics.