By Oscar Wilkins, Non-Clinical Research Fellow, University College London and The Francis Crick Institute
Hi, I’m Oscar, a newly appointed Lady Edith Wolfson Non-Clinical Research Fellow funded by the MND Association and Rosetrees Charity. I’m based at University College London (UCL) and The Francis Crick Institute. A few years ago, during my PhD studies, I wrote a blog about our team’s discovery of something called a cryptic exon in a gene named UNC13A. This was a finding that’s now helping shape new potential treatments for MND.
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What’s a Cryptic Exon?
To understand this, think of genes as instruction manuals for making proteins. These instructions are written in segments called exons. Normally, cells know exactly which exons to include. But sometimes, due to disease-related changes, the cell mistakenly includes a hidden or “cryptic” exon. Unfortunately, these hidden exons don’t contain instructions for making the protein but instead contain total nonsense. So, it’s like inserting a load of random instructions into the middle of the manual. The cells get confused by these random instructions, which prevents the protein from being produced and causes problems in the cell.
UNC13A has a cryptic exon that gets included specifically in MND. This prevents the UNC13A protein, which is really important for neurons, from being produced – we think this is a key cause of disease. The good news? We and others are developing drugs to block this error and are hopeful for a clinical trial in the next few years. UNC13A is an incredibly exciting target for MND therapies, as it is thought to be involved in most cases of MND, and therefore a successful therapeutic could be used for almost everyone with the disease.
Pietro Fratta, the Professor I work with, is a co-founder of Trace Neuroscience, a new company set up to develop UNC13A therapies for MND. Trace recently raised $100 million towards this effort, which I’ve been told is the largest initial spin-out in UCL history! Exciting times…
The Bigger Picture: TDP-43 Pathology
However, while there’s huge hope for UNC13A-based therapeutics, this gene is just one piece of the puzzle. It’s near certain that targeting UNC13A alone will not fully cure MND (rather, we hope it will slow disease progression). The real culprit behind the cryptic exon problem is a protein called TDP-43.
In 97% of MND cases, TDP-43 stops working properly. It moves from the nucleus of the cell into the cytoplasm where it forms clumps, a phenomenon known as TDP-43 pathology.
TDP-43 pathology causes a lot of other problems besides UNC13A cryptic exons and therefore many researchers believe a more successful approach might be to fix TDP-43 pathology itself.
However, TDP-43 is a complex protein. To solve such a difficult problem, one exciting approach is gene therapy, where neurons are reprogrammed by adding new genes. For example, you could add a gene which helps stop the TDP-43 from clumping together, or you could add a gene which does the same job as TDP-43 but is less likely to clump and cause disease. You could even consider adding a gene which modifies the neuron’s DNA, removing the harmful regions. The possibilities are nearly endless…if we can do it safely.
Gene Therapy and the “Invisibility Cloak”
The problem with gene therapy is that it permanently alters the genetic makeup of all the neurons. Ideally, you want the new genes to work exclusively in diseased cells and not in the 99.99999% of cells which are healthy (yes, the diseased neurons really are THAT rare, even in people with MND).
Towards this goal, I recently led a study in which we designed molecular ‘invisibility cloaks’ for gene therapies. In a healthy cell, the gene therapy stays hidden and is not produced. This is because the carefully designed DNA sequences cannot be read by the healthy cells. However, in diseased cells, the cloak is lifted, and the therapy is activated. This allows the gene’s instructions to alter the cell.
Excitingly, this cloaking approach can be used for virtually any gene therapy. Furthermore, it can be used as a biosensor. This is a tool that enables researchers to detect early signs of disease in their research models, which could be useful for screening potential treatments. We’ve already shared these biosensors with researchers worldwide, and they’re helping uncover subtle signs of MND in lab-grown neurons.
What’s Next?
We see tremendous potential in the invisibility cloak approach, not only as a powerful tool for advancing research, but also to dramatically improve the safety of gene therapies for MND. We even wonder if it could be used preventively and given to people at risk of MND due to a clear family history. The therapy would then remain cloaked and inactive until the first signs of disease appear.
During my fellowship, I’ll be refining this cloaking system, ensuring the best possible safety. I’ll also be developing new biosensors to help other researchers with their experiments. These will be very carefully tested in the best possible models of disease.
It’s an exciting time in MND research. With continued support and collaboration, I’m really hopeful this approach will open up new possibilities for understanding and treating this devastating disease.
We would like to thank Oscar for taking the time to share his exciting research with us and wish him all the best with his fellowship.
Oscar is one of the Association’s Lady Edith Wolfson Non-Clinical Fellows. These are awarded to outstanding researchers wishing to pursue a career in MND research, with a view to becoming the field’s future scientific leaders. This programme is now in its tenth year. To learn more about our fellowship program, please visit our webpage.
Oscar’s Fellowship is generously being supported by the Rosetrees Trust.
