International team advances knowledge of Huntington’s

A group of researchers from The University of Auckland who gathered at Alfred Nathan House on August 24 had more than one reason to feel satisfied.

The first was the news that they had gained approval to create the world’s first large-animal model of Huntington’s disease, allowing them to enter a new phase in their world-leading study of this devastating hereditary disease.

The second was that they had received a further injection of generous funding from the Freemasons of New Zealand, who have supported their research from its early stages.

“It can be very difficult to obtain funding when you’re working in the dark trying to get a grip on the problem,” explains Professor Richard Faull (Anatomy) who co-directs the Huntington’s team, with Dr Russell Snell.

“The Freemasons gave us an initial grant of $250,000 in 2000, which allowed us to get the project initiated.”

The Freemason’s have now given the same amount again to help in the next phase of the investigations allowing a doctoral student and a postdoctoral fellow to be added to the team.

Though the research has now progressed to a stage where other funding bodies are “coming on board” — including the United States Hereditary Disease Foundation — the Freemason’s help has been invaluable, according to the researchers.

Terry Meekan, President of the Board of Benevolence of Freemasons New Zealand, and Peter Aspden, Grand Master of the Northern Division, say they and their colleagues are “more than happy” to see the emerging results from this research. “Often we contribute money and don’t see the follow up. This time we are going to get a pay-back for helping these people fulfill their dreams. I hope the whole world will be grateful, ultimately, for this funding.”

The group at Auckland is part of a high-level international collaboration which includes scientists from Harvard University - who developed the human Huntington’s gene to be used in the research - and Professor Mark Rees - who was brought to Auckland for two years with the aid of Freemason’s funding.

Though he has now returned to take up a chair at the University of Swansea in Wales, he will continue to participate in the research from there, visiting Auckland at least once or twice a year, and co-supervising the PhD student working on the project.

The Auckland team has now entered into partnership with the state-owned South Australian Research Development Institute (SARDI) to create a flock of transgenic sheep. This could have been done in New Zealand - for example by AgResearch, which has the expertise, says Russell Snell - but would have been more expensive, with the regulatory processes taking much longer.

The flock of about 60 ewes and their descendants will carry the human Huntington’s gene, and will hopefully offer the key to new knowledge of how the disease develops.

SARDI, which uses sheep as models for many diseases, has a great deal of experience in analysing ethical issues and dealing with approval processes. This is the great value of international collaborations, says Richard Faull - that each of the partners can contribute their own specialised expertise.

Scientists at SARDI will inject a synthetic copy of the genetic mutation that causes Huntington’s disease into sheep’s embryos that have been fertilised in the laboratory.

The embryos will then be implanted into ewes, where they will grow and be born in the normal way. The researchers hope that some of these will carry the Huntington’s gene, and that this will be passed to the next generation.

When a line of sheep with the disease has been established, one each of the infected and normal sheep will be killed at regular intervals, and their brains sent for analysis to Auckland, where they will be examined for subtle, early changes.

When a patient presents with symptoms, the disease is already advanced and a lot of cell death has taken place before that time. The aim of this research is to address the changes early, before the cascade of events occurs later in the disease.

“When those subtle first neurochemical changes are taking place, the disease may be more treatable,” says Russell Snell.

The sheep, with a life-span of only five to ten years, will not live long enough to develop the unpleasant symptoms such as involuntary movement and memory loss.

A question often asked is why a sheep model is needed when a mouse model already exists.

The answer is that a sheep is much closer anatomically to a human, with a brain that more closely resembles a human brain. The fact that the sheep lives longer than a mouse also makes it more likely to manifest the early changes seen in adult-onset Huntington’s.

Mouse models, whose lifespan is only two years, show changes and develop symptoms like those of early-onset Huntington’s, a different type of condition, which develops in children

The animals will be given a rich environment during their lives, will be killed in the early stages of the disease, and will not suffer.

“We want them to run round being sheep,” says Richard.

Although the scientific and ethical approval processes, obtaining of the funding and creation of the gene construct have taken more than a year, progress from now on should be rapid, with micro-injections of the gene construct into the sheep due to take place in the next few months.

The sheep, once developed, will be made available to any scientist anywhere in the world who wishes to test a possible treatment for Huntington’s Disease.

“Our ultimate dream is to have someone with a therapeutic to test on the animals,” says Richard.

One of the driving imperatives for Richard and his colleagues is their association with the families of New Zealand sufferers of Huntington’s Disease, who have given the brains of their loved ones and shared their knowledge of symptoms to help advance understanding.

“These people are our continuing commitment,” says Richard. “Our obligation is to pursue everything that is most productive in our effort to understand and treat the disease.”

He believes that ultimately the Huntington’s model sheep may help in the study of other neurodegenerative diseases, such as Alzheimer’s and Parkinson’s Disease.

Judy Wilford

Editor – The University of Auckland News Volume 34, Issue – September 2004