Stanford Center Press Releases
Gene therapy may reverse Down syndrome
By SHARI ROANLos Angeles Times, Oct. 16, 2003
Most people know Down syndrome is a genetic disorder that causes irreversible mental retardation. But that description may not be true in the future.
Scientists have pounced on the revolutionary idea that Down syndrome -- the most common genetic cause of mental retardation -- can be treated. First, they must understand the biological cause of the condition, down to the specific genes responsible for the varied symptoms. Then, they hope, they'll be able to reverse or eliminate related problems with cognitive function, memory, speech, sleep and even the neurological decline that occurs in older adults with the disorder.
Scientists at Stanford University Medical Center already have identified abnormalities in the nerve cell structure of people with Down syndrome, differences that appear to be responsible for much of the brain damage that is the hallmark of the disorder. They're now trying to home in on the genes that cause that particular abnormality.
"People thought that once you're born with Down syndrome, that's it; you can't make the brain better. But we know that is not true about brains," says Dr. William Mobley, a pediatric neurologist at Lucile Packard Children's Hospital at Stanford. "Brains are plastic. We may not be able to cure this disease, but we may be able to make people's lives better."
Several advances have paved the way for this hypothesis. Scientists understand the brain far better than they did even 15 years ago, because sophisticated imaging devices have allowed them to better examine its structure, and the mapping of the human genome provided detailed information on the 21st chromosome. Down syndrome is caused by a third, or extra, copy of this chromosome.
The mapping of chromosome 21 revealed that it is the smallest of the 24 human chromosomes, containing about 225 genes. Now scientists such as Mobley, director of the new center for Down syndrome research at Stanford, are working to identify what those genes do.
Experiments on Down syndrome mice have shown abnormalities in the synapses, or circuits, between nerve cells. The abnormal structure and function of the synapses lead to the kind of brain damage seen in Down syndrome and Alzheimer's disease. People with Down syndrome typically develop Alzheimer's disease in adulthood, Mobley says.
Now researchers are trying to figure out which of the genes cause this problem in Down syndrome. Fixing the defect may involve turning off the extra copy of certain genes.
"We definitely know that genes cause this," Mobley says. "If we find an offending gene, theoretically we can make things better by turning off that third copy."
Treating a condition caused by an extra gene, he says, may prove easier than treating other genetic diseases such as cystic fibrosis, in which genes are abnormal or missing. Drugs could be developed to turn off that extra gene and improve cognitive ability in people with Down syndrome. Theoretically, Mobley says, the drugs could be given at any point in the life span to improve brain function.
Scientists caution that potential treatments resulting from this research are at least a decade away. But ultimately, Madnick says, "the result is going to be an individual who is much more independent, has a job, has an apartment, is a taxpayer. It's not only going to enhance their lives, it's going to enhance society."
Down's syndrome gene 'exciting'
Scientists believe they may be able to one day reverse some of the symptoms of Down's Syndrome.
BBC News, Friday, 31 October, 2003US and Swiss-based researchers have found a gene they think is responsible for mental retardation in Down's.
The team hope that a drug could now be discovered to "reactivate" a part of brain that does not work properly in patients with the genetic disorder.
However, they stress that their work is at an early stage, and any treatment would be some years away.
The human cell nucleus contains 23 pairs of chromosomes, which carry genetic information necessary for developing and running the body correctly. In Down's syndrome, the baby carries an extra copy of chromosome 21, and its presence interferes with several important body systems.
Too many genes
Unlike many gene defects, which happen because a key gene is missing, the Down's defects arise because they have an extra copy of certain genes on the third chromosome 21. This means that they are producing too much of certain body chemicals, throwing finely tuned mechanisms which govern the development and function of vital organs into disarray.Children and adults with Down's have a distinctive facial appearance. More importantly, they often have heart defects, are generally more prone to heart disease, cannot regulate temperature well in infancy, and are vulnerable to infections.
On top of this, most children with Down's have varying degrees of mental retardation.
The research team, based both at Stanford University in California and the University of Geneva, claims to have found a gene on chromosome 21 which plays a role in retardation.
In experiments in mice which have a similar genetic fault - and which share many genes with humans - they have found a gene which appears to hinder the transport of an important brain chemical into a certain part of the forebrain. This has already been linked with retardation.
Reversal of fortune
Chemistry and Industry reports that this gene could now be the target for drugs to "downregulate" the action of the extra gene - although these drugs are some time away. Remarkably, there is some hope that a drug to reverse this gene defect could actually reverse retardation to some degree even in adults.This area of the forebrain does not require new brain cells - it already has cells, but they are simply not working properly. The theory is that a drug to restore their proper activity could have a marked effect.
Professor William Mobley, from Stanford University, said: "We definitely think we are on the right track to restoring memory and learning in individuals with Down's syndrome. "With the perfect drug at the right dose, we can reduce protein production by the extra copy of the gene. We think that this could reverse mental retardation."
No certain improvement
However, this is far from certain, as no-one knows how newly-reactivated neurons would behave, or how they would fit into the wider workings of the brain. Professor Mobley said that it was possible there would be absolutely no effect whatsoever.Dr Jonathan Cooper, from the Institute of Psychiatry, told BBC News Online: "If it's a single gene involved in the degeneration of these cells, then it should be possible to target it, although this may be technically complicated to do. However, if you can restore these cell populations, it would be important to know that they are fully functional, which presently remains unclear. This is a very good research team and this idea shows great potential - although it is at a very early stage. There is likely to be some way to go before this can translate into treatments in humans."
A spokesman for the Down's Syndrome Association told BBC News Online: "The findings of William Mobley and his team are interesting and we would welcome anything that improves the lives of people with Down's syndrome. However, although this work appears to be at a very early stage, with no effective treatments likely in the foreseeable future, we plan to be in communication with the team to see if there is any opportunity for us to give our support. "