Silencing the messenger in Huntington’s disease
Using viruses to deliver treatment inside the body
Fundraisers and donors support neuroscience and mental health researchers as they seek to improve diagnoses and treatments for a wide range of neurological conditions. Researchers can receive support towards equipment, research travel expenses, and ‘seedcorn’ grants that enable them to test new hypotheses.
This ‘seedcorn funding’ lets researchers follow a hunch or explore a new idea before applying for more substantial grants. By giving in this way, donors, fundraisers, and gifts left in Wills unlock new targets for cancer research and new opportunities for treatment.
We have known the cause of Huntington’s disease for over 30 years. It is neurodegenerative and genetic – caused by a mutation in a gene. Its symptoms vary from involuntary movements, dementia or psychiatric alterations. Symptoms often begin when the carrier is around 40-50 years old – but the weight of knowing that it could develop is heavy for many who live with the mutation, long before symptoms manifest.
It has taken a huge global effort to get research to the current stage – where some potential treatments are being tested in early clinical trials. But there is still a lot of work to do.
In Cardiff, we have researchers working on Huntington’s disease from many perspectives. This ranges from the development of cell and gene therapies, to researchers who are trying to understand and better treat the psychiatric and cognitive aspects of the disease.
We also work to try to improve the ways in which we can detect change in people with Huntington’s, either using blood tests or scans, and to develop better and more efficient ways of doing clinical trials in Huntington’s.
Dr Álvaro Murillo-Bartolome wants to spend his career finding a cure. He has been researching Huntington’s disease since working in a lab as part of his biology degree. Now he’s combining his knowledge of biology and biotechnology to research possible treatments.
“The severity of the disease depends on the number of mutations. C-A-G-T are the building blocks of DNA. In people without Huntington’s, the CAG segment is repeated around 20 times, but in Huntington’s patients, there are 40 to 120 repeats. These repeats are what cause the symptoms and the damage of Huntington’s disease. We want to reduce the number of mutations, to prevent and reduce Huntington’s symptoms. To do this we use viruses and gene editing tools.
“Viruses are like vehicles. Often, they act like vehicles being driven by monkeys! If we take the monkey out, taking away the virus’ propensity to damage things, but leaving its ability to infect neurons in the brain, we can use viruses to deliver treatment inside the body – and then the immune system will dispose of it once it’s no longer useful.
“Thanks to funding from donors and fundraisers I’ve been able to develop a virus, taking away its harmful properties. Instead we can give it the capability to carry a gene editing tool (CRISPR) right to the mutations to take them away. In theory, we could inject this virus into the brain one time – no need to go through multiple stages of treatment – and the neurological symptoms would decrease. Depending on when you give the injection, you could rescue remaining unaffected neurons or even prevent neuron death.”
This idea, though ground-breaking, has its limits. Due to current medical ethics, it would not be able to get to clinical trial yet but will be a proof of concept for Álvaro and his colleagues. So Álvaro is investigating a second option for treatment using viruses.
“It needs much more refining and remains a theoretical environment – but still one of great value. And so I’m now using further donor funding to employ viruses at a different stage in the disease development.
“You see, our DNA acts like an instruction manual and the proteins in the gene are the workers. RNA is the middleman: the messenger which takes the instructions from the DNA to the proteins. In my first project I am trying to change the instruction manual by editing the DNA. In this second project I am trying to silence the messenger – the RNA – to stop the faulty instructions from getting relayed and followed.
“There are two copies of the gene that is significant in Huntington’s. One copy is mutated and the other is not. The RNA is so similar in these two copies at the RNA level that current ideas regarding treatment can’t distinguish between the healthy and not healthy cells.
“My goal is to develop a virus that can differentiate between the two copies and use CRISPR again but this time to silence the pathological (harmful) copy. This would stop the instructions from getting followed by the gene and would stop Huntington’s symptoms from developing.”
Álvaro’s research is exciting, and has the potential to change the lives of patients and families. But he knows well the importance of getting this science right, at the right pace.
“Research takes time. It involves much waiting, and much patience, which is difficult when you know people are living with the knowledge of their mutations and the knowledge that the symptoms begin at any time in their lives.
“This research could be not only transformative for Huntington’s disease patients, but by discovering more about RNA, this could unlock answers for 40 other diseases.”
“When there are no new ideas, everything stays the same. We need initiative in this field, we need freshness. And these new ideas need first steps to prove their potential for further research. Thank you for giving my research these first steps.”
— Dr Álvaro Murillo-Bartolome
“Donors to these seedcorns – these smaller funds that can lead to further grants and projects – give early career researchers the opportunity to develop our own ideas. Without seedcorn funding this is almost impossible.”
Many of our neuroscience and mental health researchers across the University are being supported by donors, fundraisers, and those leaving gifts in their Wills. You are transforming understandings of disease and fuelling research for cures.
