Huntington’s disease strikes the central nervous system. The symptoms range from involuntary movements to depression and cognitive difficulties. Although medication can help with the symptoms to some extent, it is a relentlessly progressive disease that is impossible to halt completely. Molecular biologist Ulf Andersson Vang Ørom wants to change this. A researcher in RNA Biology and Innovation at the Department of Molecular Biology and Genetics at Aarhus University, he has just received a Frontier Grant of DKK 4.3 million from the Lundbeck Foundation.

Along with his colleague Veronica Brito from the University of Barcelona, Ørom will seek to pave the way for RNA-targeted treatments for Huntington’s disease. The idea is to prevent the genetic error code that causes the disease from being converted via RNA into protein aggregation in the cells, which leads to cell death. Ørom looks forward to getting started.

‘I’ve had this project in mind for a long time, but it’s been difficult to get it off the ground because targeting RNA this way is a radical new approach.’

This type of innovative research with the potential to culminate in new forms of treatment is precisely why the Lundbeck Foundation introduced Frontier Grants in 2022.

’Ulf’s project is a prime example of the kind of work we want to support with this new type of grant. The project is innovative and could make a significant difference if the next steps are as successful as we hope. Whenever you take the lead, you run the risk of things not working out quite as expected. But it’s vital that someone is willing to take the risk – otherwise, we will never get anywhere,’ says Paul E.G. Kristjansen, MD, PhD, Senior Scientific Director responsible for Frontier Grants at the Lundbeck Foundation.

Many people are familiar with RNA from the mRNA vaccines developed during the COVID-19 pandemic, but medicines specifically targeting RNA are a whole different matter. RNA medicines differ from other treatments in that they alter or eliminate RNA, which affects the cells’ functions.

Just as we have DNA in every cell of the body, we also have RNA, which takes different forms and fulfils other functions. The best known is messenger RNA (mRNA), molecules that read the gene sequence ‘recipes’ for the proteins involved in many of the cells’ processes. This function makes mRNA particularly relevant to Huntington’s disease, in which proteins play a crucial role. It is hereditary, and unless both parents have it, their children will have one healthy and one diseased copy of the gene.

It may be possible to identify the genetic defect, but so far, it has proven impossible to tell the difference between healthy and diseased mRNA. Supported by the Lundbeck Foundation, Ørom has now made an important discovery. He has shown that in mice, the structure of the diseased mRNA differs from the healthy mRNA due to so-called “modifications”, i.e. chemical changes.

It is normal for mRNA to undergo thousands of modifications, but some of them in diseased mRNA are unique and expressed in a different chemical structure, making it possible to identify the diseased mRNA and target it with medication.

’mRNA usually has a good, well-defined structure, which folds a certain way. But modifications to the diseased mRNA change that structure and make it more unstable, which has an impact on its function. In the case of Huntington’s, this can lead to protein aggregation in the cells.’

Ørom has also identified certain molecules that can attach to the specific structure of the diseased mRNA. If these molecules can also neutralise or break down mRNA, it may be possible to curb the production of the pathogenic protein in people with Huntington’s disease. It also means that it may be possible to do so without damaging the cell itself or the healthy mRNA. Selectively removing the pathogenic mRNA is a brand-new approach. In previous trials with patients, other researchers have eliminated both the healthy and diseased mRNA.

’Afterwards, the patients did not feel well, so the healthy mRNA has to be there. The challenge lies in removing only the diseased mRNA,’ he explains.

The researchers will use the grant money to confirm that the modifications found in mice are also present in humans. This will involve studying the brain tissue of deceased patients. Next, they need to show that the RNA treatment can target diseased mRNA and that it is possible to produce the medicine.

‘We already have data from animal models and early clinical data. This project aims to gather solid clinical data and more data on drug development,’ says Ørom.

If all goes well, the project will pave the way for the development of medication for Huntington’s, probably in tablet form. But the ambitions extend beyond just this one disease.

’I want to show we can use disease-specific RNA modifications to create new targeted medicines for several diseases. For example, we have also seen modifications in cancer cells. If we can use the cancer-specific modification profile to remove the RNA needed for the cell to divide, we can produce RNA drugs capable of inhibiting the division of cancer cells,’ he explains.

Although research into RNA modifications is still in its infancy, Ørom expects new treatment options to emerge as more modifications are studied.

’We now have methods to identify RNA modifications – and we’ve realised that RNA is far more complex than previously thought. The research is opening up new perspectives.’

Associate Professor Ulf Andersson Vang Ørom

Department of Molecular Biology and Genetics
Aarhus University, Denmark
ulf.orom@mbg.au.dk - mobil 22288766