Liana Lareau

Engineering Poison Exons to Treat Repeat Expansion Diseases

This project focuses on developing kill switches to deactivate disease-causing genes, particularly focusing on challenging conditions like Huntington’s disease. Standard CRISPR approaches for these conditions have limitations. Instead, the project proposes a novel method utilizing machine learning and CRISPR editing to insert ‘poison exons’ into disease genes. These exons, when incorporated into mRNA, eliminate toxic proteins responsible for the disease. This approach offers a versatile platform for targeting various genetic diseases, particularly repeat expansion disorders.

Targeting Genetic Diseases with CRISPR to “Turn Off” Harmful Genes

Updated February 10, 2025

By: Niki Borghei

CRISPR holds the promise to revolutionize the way we treat genetic diseases – and we are just getting started exploring its potential.

Liana Lareau, Assistant Professor in the Department of Bioengineering, is on the brink of a medical breakthrough that could change the way we approach some of the most challenging genetic diseases, including Huntington’s disease.

Huntington’s disease is a devastating disorder, caused by a dominant-negative mutation in a single gene. Unlike many genetic conditions that require both copies of a gene to be faulty, Huntington’s can strike with just one copy of the defective gene — inherited from either parent. This mutation leads to the production of toxic proteins that gradually destroy brain cells, resulting in the progressive decline of motor control, cognition, and ultimately, life itself. For those affected, the prognosis has historically been grim, with no cure in sight.

But what if there was a way to stop the disease at its source? Lareau’s project is exploring exactly that. Her work is grounded in a simple, yet powerful idea: what if we could use CRISPR, the revolutionary gene-editing tool, to “turn off” the disease-causing gene?

Q: Does this technology only apply to diseases like Huntington’s Disease, or is there a potential to treat other diseases, too?

A: We think that our platform idea can apply to many, many diseases. It may not apply to every disease and every patient, but this platform can likely target multiple different mutations.

Q: “Turning off” a disease sounds almost too good to be true! How did you develop the idea for this approach?

A: My background in computational biology started out with understanding the basic rules of how our genome sequence can possibly contain all the information we need to make us who we are. I got my start right around the time the Human Genome Project was published. The past two decades of my work, and the field more largely, were about establishing a basic understanding of how these things work. But along the way we found some unexpected things about how genes are controlled. I realized that now we are at a turning point. We can combine the computational models and our understanding of molecular biology with CRISPR to start fixing problems.

Q: How did you decide to pursue entrepreneurship?

A: We’re at an exciting point of heightened synergy between academic research and biotech. Up until now, we have been largely focused on building the basic knowledge of what CRISPR can do, and now, we are finally able to apply that research to therapeutics and cures. I feel like entrepreneurship is the right next step when you are at the point when your research can make a real difference.

Q: How will the Spark Award support your project?

A: We’re using it to build up some of our basic preliminary data, identifying disease genes that are the best candidates to start out with for this approach. The Spark Award is supporting both computational and wet lab work in my lab. This allows us to explore many different directions at once while also building a compelling set of data.