Activity of Huntington's disease gene curbed for six months in mice

September 9, 2016 by Hayley Dunning
Healthy brain (L) and Huntington's brain (R). Credit: Imperial College London

A single injection of a new treatment has reduced the activity of the gene responsible for Huntington's disease for several months in a trial in mice.

Huntington's disease is a genetic disorder that affects around 1 in every 10,000 people and damages nerve cells in the brain. This causes neurological symptoms affecting movement, cognition and behaviour.

Huntington's usually only begins to show symptoms in adulthood. There is currently no cure and no way to slow the progression of the disease. Symptoms typically progress over 10-25 years until the person eventually dies.

Now, the EU-funded FINGERS4CURE project team led by researchers at Imperial College London have engineered a therapeutic protein called a ''.

Huntington's disease is caused by a mutant form of a single gene called Huntingtin. The zinc finger protein works by targeting the mutant copies of the Huntingtin gene, repressing its ability to express and create harmful proteins.

In the new study involving mice, published in the journal Molecular Neurodegeneration, the injection of zinc finger repressed the mutant copies of the gene for at least six months.

In a previous study in mice, the team had curbed the 's activity for just a couple of weeks. By tweaking the ingredients of the zinc finger in the new study they were able to extend its effects to several months, repressing the over that period without seeing any harmful side effects. This involved making the zinc finger as invisible to the immune system as possible.

A lot of promise

Project lead Dr Mark Isalan from the Department of Life Sciences at Imperial said: "We are extremely excited by our latest results, which show a lot of promise for treating Huntington's disease.

"However, while these encouraging results in mice mean that the zinc finger looks like a good candidate to take forward to human trials, we still need to do a lot of work first to answer important questions around the safety of the intervention, whether repeat treatments are effective, whether there might be longer-term side effects, and whether we can extend and increase the benefits beyond six months.

"In this study we weren't looking at how repressing the affected the symptoms of the disease and this is obviously a critical question as well. However, we have reason to be confident from our previous studies that repressing the gene does in fact significantly reduce symptoms.

"If all goes well and we have further positive results, we would aim to start clinical trials within five years to see whether the treatment could be safe and effective in humans. We are urgently looking for industry partners and funding to achieve this."

Cut off at the source

The mutant Huntingtin gene is thought to cause toxic levels of protein to aggregate in the brain. Preventing the activity of this gene could theoretically halt the disease, but this has been difficult to achieve.

The gene is present in many different cell types in the brain, making it difficult to target, and every patient also has a non-mutant copy of the gene, which scientists need to avoid targeting with any intervention in order to prevent unwanted side effects.

The zinc finger protein sticks to the DNA of the mutant Huntingtin gene and turns off the gene's expression. "We don't know exactly how the mutant Huntingtin gene causes the disease, so the idea is that targeting the gene expression cuts off the problem at its source – preventing it from ever having the potential to act," said Dr Isalan.

By targeting the fundamental DNA of the gene, the zinc finger therapy also has the advantage over other potential Huntington's therapies of needing less frequent treatments.

Lengthening effect

In the study, the researchers gave a single injection of zinc finger to 12 mice with Huntingdon's disease. They examined the brains of the mice at different intervals after the initial injection and found that on average, 77 per cent of the 'bad' was repressed in mouse brains three weeks after injection of the zinc finger, 61 per cent repressed at six weeks, and 48 per cent repressed at 12 weeks.

By 24 weeks after the initial injections, there was still 23 per cent repression, which is thought to still be useful therapeutically. The team are now working on ways to lengthen the repression period even further.

Explore further: Huntington's disease gene dispensable in adult mice

More information: Carmen Agustín-Pavón et al. Deimmunization for gene therapy: host matching of synthetic zinc finger constructs enables long-term mutant Huntingtin repression in mice, Molecular Neurodegeneration (2016). DOI: 10.1186/s13024-016-0128-x

Related Stories

Huntington's disease gene dispensable in adult mice

March 7, 2016
Adult mice don't need the gene that, when mutated in humans, causes the inherited neurodegenerative disorder Huntington's disease.

Scientists tackle Huntington's disease by targeting mutant gene

November 6, 2012
Huntington's disease is an inherited, neurodegenerative disorder that usually appears in mid-adult life and leads to uncoordinated body movements and cognitive decline. The disease is due to multiple repetitions of a deoxyribonucleic ...

Scientists develop test to measure effectiveness of treatments for Huntington's disease

August 7, 2015
A new test developed by UBC researchers allows physicians to measure the effects of gene silencing therapy in Huntington's disease and will support the first human clinical trial of a drug that targets the genetic cause of ...

Potential therapeutic target for Huntington's disease

August 16, 2016
There is new hope in the fight against Huntington's disease. Scientists at the Gladstone Institutes discovered that changing a specific part of the huntingtin protein prevented the loss of critical brain cells and protected ...

Protein subunit found to rescue afflicted neurons in Huntington's disease

September 5, 2016
Using an experimental co-culture approach in which two different types of neurons from a mouse model of Huntington's disease (HD) are grown side-by-side, connecting to form critically impacted circuits, researchers at University ...

Broken cellular communication in brain contributes to Huntington's disease symptoms, study finds

April 7, 2015
Indiana University researchers have found that broken communication in a specific part of the brain plays a role in the involuntary physical movements that affect individuals with Huntington's disease.

Recommended for you

Investigating patterns of degeneration in Alzheimer's disease

November 17, 2017
Alzheimer's disease (AD) is known to cause memory loss and cognitive decline, but other functions of the brain can remain intact. The reasons cells in some brain regions degenerate while others are protected is largely unknown. ...

Study may point to new treatment approach for ASD

November 17, 2017
Using sophisticated genome mining and gene manipulation techniques, researchers at Vanderbilt University Medical Center (VUMC) have solved a mystery that could lead to a new treatment approach for autism spectrum disorder ...

Paraplegic rats walk and regain feeling after stem cell treatment

November 16, 2017
Engineered tissue containing human stem cells has allowed paraplegic rats to walk independently and regain sensory perception. The implanted rats also show some degree of healing in their spinal cords. The research, published ...

Brain implant tested in human patients found to improve memory recall

November 15, 2017
(Medical Xpress)—A team of researchers with the University of Southern California and the Wake Forest School of Medicine has conducted experiments involving implanting electrodes into the brains of human volunteers to see ...

Researchers identify potential mediator for social memory formation

November 15, 2017
Research by a group of scientists at the Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore (NUS Medicine) have discovered that a tiny brain region plays a critical role in the formation ...

Improving clinical trials with machine learning

November 15, 2017
Machine learning could improve our ability to determine whether a new drug works in the brain, potentially enabling researchers to detect drug effects that would be missed entirely by conventional statistical tests, finds ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.