Unleashing splicing to understand biology and eventually tackle ‘untreatable’ diseases

The same thing is happening – at the molecular scale – inside every human cell. Cells are like eccentric filmmakers, using a process known as alternative splicing as their creative tool. Just how movie producers use an editing toolbar to rewind, speed up or cut a scene entirely, cells use their editing tools to swap, skip or include specific DNA segments in messenger RNA. This ability allows cells to alter gene expression, or create slightly different versions of a protein with unique functions.

Humans have roughly 20 thousand genes within our genomes, but thanks to alternative splicing, cells can make many more proteins than the number of genes. This expanded catalogue of proteins helps cells both adapt to changing environments and carry out more complex functions. It is thought that almost 95% of human genes undergo alternative splicing of some sort.

Knowledge of alternative splicing can be used to reveal new therapeutic targets and treat diseases that were previously considered incurable. For example, spinal muscular atrophy is one of the leading causes of infant mortality, a disease caused by mutations in a gene known as SMN1. People living with the condition have insufficient levels of the survival motor neuron protein, which leads to loss of motor neurons in the spinal cord and causes weakness and wasting of the skeletal muscles. The medication nusinersen – the first drug approved to treat the disorder, with life-saving effects – compensates for the loss of function of SMN by modulating alternative splicing of the closely-related SMN2 gene, functionally replacing the defective SMN1 gene.

Despite the emerging success of splicing-based therapies such as nusinersen, the mechanistic understanding of how small molecule drugs can modulate alternative splicing remains very limited. Small molecule drugs have distinct advantages as therapeutics as they can be administered orally and pass through cell membranes to reach the cell nucleus, where alternative splicing takes place. To accelerate the discovery of therapeutic targets for other diseases previously considered untreatable, researchers require new experimental tools and methods to study the underlying biological mechanisms involved.

This is the objective of UNLEASH, a new collaborative research project that begins operations today. Supported by a 10.2-million-euro Synergy Grant jointly funded by the European Research Council (ERC) and UK Research and Innovation (UKRI), the UNLEASH project aims to identify and develop new small molecules that can eventually function as drugs and control which types of alternative splicing events take place in cells. The project is expected to last for a period of six years.

“Video editing tools will include hundreds of buttons, ranging from play, pause or fast forward to more advanced functions. Our first step is to uncover the equivalent of these functions available to cells, so that we know what they are capable of in the first place. The next step is figure out how to press the buttons so we can manipulate the editing tool for therapeutic purposes,” says ICREA Research Professor Juan Valcárcel, senior researcher at the Centre for Genomic Regulation and coordinator of the UNLEASH project.

The project will combine the complementary expertise in the research groups of David Gray and Angus Lamond (University of Dundee), Michael Sattler (Helmholtz Munich) and Juan Valcárcel (Centre for Genomic Regulation, Barcelona), employing an interdisciplinary approach that combines chemical, structural, cellular, and systems biology methods, along with deep learning computational approaches.

In the long term, the researchers will identify, develop and improve small molecules that can selectively alter alternative splicing events, characterizing compounds bound to splice site complexes, and testing mechanistic models of splice site selection. “With our project, we hope to to unleash the unique potential of small molecules as splicing modulators to develop orally available drugs for treating diseases with unmet medical need” says Michael Sattler, senior researcher at Helmholtz Munich. The resulting data will be used to train neural networks to predict changes in alternative splicing patterns and the effects of small molecule modulators.

“While we might never know what drives the creative process behind a movie director’s vision, the same process within cells might be more of a tractable problem than we previously thought. If we solve this, it can open a whole new world of possibilities,” concludes Dr. Valcárcel.