Hunting down Huntington’s Disease.

John writes ...

First, some cool science.
I am sure that all our readers are familiar with the central facts of molecular biology, namely that genes are copied into molecules called messenger RNA (mRNA) and that the code in mRNA is translated by the cell in order to make proteins (see pages 115-121 in the book). You will also be aware that genes can be switched on and off, so that for example, when a particular protein is no longer required, the gene that encodes it is switched off. But there is a problem: many mRNA molecules are fairly stable; they remain in the cell after the relevant gene is switched off and thus, the now unwanted protein can still be synthesised.

​However, mechanisms have evolved to deal with this problem. Cells are able to synthesise various different types of RNA which are complementary to part of the sequence of the relevant mRNA, thus base-pairing with it, forming a short section of double helix in the mRNA. This inhibits the mRNA from being translated and marks it for de-activation and/or degradation. Different genes make use of different types of these inhibitory RNAs; the type I want to focus on here is microRNA. Please keep this in the back of your mind for recalling later in this blog post.

Huntington’s Disease.
Huntington’s Disease is a very distressing neurodegenerative condition caused by a dominant mutation in the HTT gene that encodes an essential brain protein called huntingtin (Htt). The mutant protein does not function properly; it accumulates in neurons and eventually causes death of neuronal cells. Because the mutation is dominant, the offspring of anyone with the gene have a 50% probability of having the condition. Further, as the gene is passed down the generations, so the age of onset becomes earlier. For example, I once met a man in his mid-30s who was already showing signs of the disease. The way the disease develops has been described as a combination of motor neurone disease, Parkinson’s disease and dementia. Personality and behavioural changes often occur in the early stages, as exemplified in a conversation I had several years ago (at Lee Abbey in fact) with a woman whose husband was becoming increasingly verbally aggressive and angry as the disease started to take hold.

A representation of the structure or huntingtin from Kim, M.W. et al., Structure Vol. 17, pp 1205–1212 (2009).

At any one time in the UK, there are about 6,700 people at various stages of progression of the disease which equates to about one sufferer in every 8,065 people. That may not seem many but for individual patients and their families that is irrelevant. The degree of suffering they experience is immense and it matters not how many or how few other sufferers there are. But there is hope, as I discuss in the next section.

A cure for Huntington’s Disease?
Yes: in the past two days (I am writing on September 25th) there has been an amazing announcement, followed by appropriate commentary, that a cure has indeed been developed. The key players in this work are a research team at University College Hospital, London, led by Professors Ed Wild and Sarah Tabrizi, in collaboration with uniQure NV, a Dutch pharmaceutical company that focuses on gene therapy.

Professor Ed Wild and Professor Sarah Tabrizi. Photo by Fergus Walsh/BBC.

So, how did the team develop a cure? Is it possible to inactivate the mutant gene whilst leaving the normal gene working properly? Yes it is, but not in a way which works directly with genes at the level of DNA. Referring back to the first paragraph, the sequences of the mutant and normal messenger RNAs are different enough to allow the research team to make a microRNA that is specific for the mutant message. In other words, it is possible to specifically target the mutant mRNA for inactivation/degradation. The next challenge is to deliver a consistent supply of the microRNA to a patient’s brain cells. This challenge was met by a ‘slice’ of pure genius. A tiny gene, a very short piece of DNA encoding the microRNA, was synthesised and inserted into a benign virus which was infused into the brains of the 29 people taking part in the trial. That process in itself was very complex, as described in the BBC’s report on this work (Huntington’s disease successfully treated for the first time) and brought about what was, in effect, genetic modification of the brain cells enabling them to make their own supply of the microRNA. 

The microRNA/gene therapy method used to combat Huntington’s disease. Credit: BBC Research.

Three years on from this procedure, the results for patients have been remarkable. Disease progression has been slowed by 75% while death and loss of brain cells have been dramatically reduced. Patients who expected to be in wheelchairs are still able to walk and one who had retired on health grounds has been able to return to work. Whilst this not a complete cure, it is still an amazing result and holds out hope that with a bit of tweaking, that 75% may be improved on. It also raises hopes for people who know they have the mutant gene but who are not yet showing symptoms, exemplified by Jack May-Davis who featured in the BBC report. He is 30 years old but recalls that his father first showed symptoms when he was in his late 30s and died at the age of 57. Having been one of the 29 taking part in the trial, Jack stated that this "breakthrough has left him overwhelmed" and that he can envisage a future that "seems a little bit brighter, it does allow me to think my life could be that much longer".

Brain scans of, on the left, a healthy person and on the right, a person with advanced Huntington’s disease. The loss of brain matter caused by the death and degradation of brain cells is very clear. Credit: University College Hospital, London.

Jack May-Davis. Photo by Fergus Walsh/BBC.

Epilogue.
I am thrilled by this work for two reasons. Firstly of course, because it brings hope to those who have the mutant Huntington’s gene, whether or not they have yet developed symptoms. Secondly, I am thrilled because this is a brilliant use of good science in the service of humankind. The various inhibitory RNAs, of which microRNAs are one type, are relatively recent additions to our knowledge of how genes work. That knowledge was acquired by curiosity-driven research on gene expression as scientists worked, without any ‘commercial’ or ‘applied’ agenda, to reach a greater understanding of the fundamentals of molecular biology.

Postscript.
As I wrote this post, it was clear that this news had gained a large amount of attention, with reports appearing across a wide range of print, broadcast and digital media. This even involved me because shortly after I started writing, I was invited (and accepted the invitation) to give an interview about the work on Trans-World Radio (UK).
 

John Bryant
 
Topsham, Devon
 September 2025