Harnessing the splicing code for targeted control of gene expression

Introduction

Alternative splicing (AS) of mRNA precursors plays important roles in tissue-specific gene regulation and biological regulatory mechanisms, as it can radically alter protein expression, cell phenotypes, and physiological responses. Altered splicing also contributes to disease mechanisms, ranging from neurodegeneration to cancer.

Therapeutic Potential

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.

Knowledge Gap

Unfortunately, despite decades of research, a comprehensive understanding of the mechanisms that control the specificity of AS is lacking. This gap in basic knowledge prevents opportunities to harness splicing modulators as tools to study gene function, novel therapeutics, or other biotech applications.

Project Overview

This Project addresses head-on the major technical challenges that have limited progress in the AS field. Building on extensive preliminary data, we will use a multidisciplinary approach that combines:

1. Chemical
2. Structural
3. Cellular
4. Systems biology
5. Machine learning

to characterize mechanisms of splice site selection and identify targets for modulating these mechanisms using tool compounds.

Expected Outcomes

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. This will enable future applications harnessing splice site selection.

Central Question

Our primary goal is to answer the central question, ‘Is it generally 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.