Gene therapy for MND funded by Advancing Treatment Award
09 October 2024
09 October 2024
We are funding three researchers developing new treatments for MND this year through our Advancing Treatments Awards. With our funding, Dr Younbok Lee of King’s College London will develop a gene therapy to correct a mutation in DNA that causes around 40% of familial MND cases.
Inherited or “familial” MND
A minority of MND cases are inherited. Specific mutations – changes in our DNA – cause these cases of MND. Mutations in a gene called C9orf72 cause two out of five cases of inherited MND. Dr Lee, working with a team including research associate Dr Doyoung Lee, plans to develop a gene therapy to reverse these mutations.
The gene therapy approach
The mutations in C9orf72 that cause MND aren’t easy to fix. They are literally written into DNA. This acts like a set of blueprints that the cell reads to make a protein, also called C9orf72. The mutated version of this protein causes damage to key cell systems, which leads to the death of motor neurons.
To fix this, Dr Lee plans to use genetic tools to bind and destroy the ”messenger RNA” that is made from C9orf72’s genetic blueprints, preventing the mutated C9orf72 protein from being produced and damaging the cell. While other attempts have been made to shut down these molecules, Dr Lee’s approach will be more comprehensive.
Dr Lee believes removing the mutated protein isn’t enough to repair MND-affected motor neurons. He plans to use a harmless virus called an AAV (adeno-associated vector) to infiltrate affected cells and add corrected genetic blueprints for the C9orf72 protein. “Designing a gene therapy is like building a rocket,” said Dr Lee. “The AAV is like the hard outer shell of the rocket, while the new and improved genetic instructions are like the rocket’s precious cargo.”
If this cargo can be delivered successfully, affected motor neurons should start producing healthy protein, which can perform its normal role in the cell and restore its function.
This approach is two-pronged. It prevents the creation of the mutant project which damages the cell and fixes the original gene mutation in C9orf72 that causes MND at its root. Dr Lee hopes that this combination approach will prove more effective than previous therapies targeting C9orf72.
Why is this research important?
If a treatment could reverse these disease-causing gene mutations, then MND could be preventable and treatable for a small number of patients. Importantly, these learnings could then go on to help other people living with MND who have other gene mutations or who have non-inherited disease.
Gene therapies have been developed for other diseases, meaning that Dr Lee’s work has a springboard of success to accelerate development. Dr Lee said, “When humans first designed rockets, we failed several times. But these attempts weren’t really failures, because we learned from the failure so that we could eventually succeed. It’s the same in this field. This funding will be very, very important to allow our scientists to aim higher. Without it, we could only imagine what a successful therapy would look like. But now, we can make these therapies real; we want to shoot for the moon.”
Jessica Lee, Director of Research at My Name’5 Doddie Foundation said, “C9orf72 biology is very complex and not yet completely understood. Whilst previous attempts to target the C9orf72 gene have failed, we hope that Dr Lee’s innovative approach will overcome the challenges that have been faced to date. Importantly, this project should also teach us more about C9orf72 biology and therefore add to our growing understanding of MND.”