HD research news - medical research into treatment & prevention

The mouse brain can cure itself

Reproduced from the Hereditary Disease Foundation Newsletter

August 2000

The mouse brain can cure itself of HD - if you give it a chance!! So found Columbia University researchers Ai Yamamoto, Jose Lucas and Rene Hen, supported entirely by Hereditary Disease Foundation funding. The Columbia scientists wanted to learn if an animal - or better yet a person - can cure itself of Huntington’s symptoms, once the disease has started. Is it possible to tum the gene off and stop the HD gene protein from being made? Can a mouse - and hopefully a person - cure itself even after symptoms have started?

In order to answer the question "is Huntington’s disease reversible, once it begins? " they designed an extremely clever experiment. The scientists "genetically engineered" a piece of the human HD gene with a kind of "genetic switch." This "switch" enabled them to turn the HD gene on and off at will. We know that mice, and probably humans as well, need the protein made by the HD gene - called "huntingtin" - to survive. The investigators left the mouse’s own huntingtin protein intact. But in addition to the mouse huntingtin protein, the scientists placed into the mouse embryo the human HD gene, connected to their "switch." At first they left the human HD gene on to make its "toxic protein." This protein began to make the mice sick, just as it makes humans sick. The mice have abnormal motor coordination and, even more significantly, they have changes of important chemicals in the brain and the development of sticky clumps or "aggregates" that seem to clog up the works in the brains of people and mice with HD.

After five months, Ai and René "flipped the switch." They turned the human HD gene off so that no abnormal human HD protein was made! They continued to watch the mice for another four months and to compare these mice to their litter mates in whom they had not flipped the switch. In other words, half of the mice stopped making the HD protein, while half of the mice continued to make it.

Much to their amazement, the mice that were no longer producing the abnormal protein began to recover their functionality! Before the eyes of the shocked investigators, the mice seemed to get well! Even more dramatic were the changes in the mouse’s brain. Where clumps had appeared in the brain cells of the sick mice - suddenly these clumps had disappeared! And even more surprising, some of the biochemical abnormalities had even recovered! Who knows what would have happened if the investigators had continued to let the animals improve for longer than four months.

This discovery is very good news - for mice, men and women! It means that the brain has restorative powers of which we little dreamed! If we can figure out a way to stop the abnormal HD protein from being made, we will have a cure for Huntington’s! But even more gratifying is the knowledge that if we can stop the protein from being made even in people who have been affected for some time - they should anticipate at least some degree of recovery. This elegant, imaginative and even brilliant research is enormously encouraging to all of us.

The paper was accepted in the journal Cell - one of the most prestigious science journals in the world. It rated a "Commentary," an honour afforded to only a few articles in the joumal. Science Advisory Board member Huda Zoghbi, along with fellow researcher Harry Orr, wrote in the Commentary "that the brain has abilities of which biologists know little."

Our heartfelt congratulations and gratitude go to these dynamic and dedicated investigators. Rene Hen, a superb scientist, is an Associate Professor of Pharmacology at Columbia University. Jose Lucas began the work when he was a post-doctoral student in Rene’s lab and then retumed to Spain and is continuing to work on some aspects of it. Amazingly enough, Ai Yamamoto took over this extremely challenging research as her graduate thesis work. Needless to say, Ai will graduate with flying colours, but right now she is hard at work - talking to the mice every day trying to learn their secrets for curing themselves of HD. As soon as she learns the secret, she will certainly pass it onto us and we will pass it onto you and the world will rejoice!