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Internaf Newsletter December 1999 Issue
Page 4 Page 1 Page2 Page3 News Index
New Treatment Hope for the Ataxias M edical researchers have uncovered a new clue to help explain how some crippling diseases damage nerve cells, a discovery that could lead to new treatments for conditions like Huntington's chorea.In separate papers appearing in Friday's issue of the journal Cell, two research teams reported that such illnesses seem to appear only when a key protein in a nerve cell slips into the nucleus, the control centre of the cell. When the researchers used genetic engineering techniques to prevent the accumulation of material in the nucleus, there were no signs of Huntington's, which causes rapid, jerky movements and relentless mental deterioration in 1 in 20,000 people.The teams worked on inherited diseases caused by a stuttering of the genetic code, where a section of the code is repeated too many times. If there are more than 40 or so repetitions, symptoms eventually appear. But how the repeated sequences translate into an illness remains a mystery.Researchers, led by Harry Orr of the Institute of Human Genetics at the University of Minnesota, discovered that if they could prevent a protein known as ataxin-1 from entering the nucleus, they could block the development of symptoms similar to a group of human diseases known as spinocerebellar ataxia's.The ataxias diseases affect about 1 in 50,000 people and attack the same portion of the brain that causes intoxicated persons to stagger. "Some have to carry cards around saying they are not intoxicated,'' and instead suffer from the disorder, Orr said in a telephone interview. The second study involved Huntington's chorea, a condition characterized by a gradual decline and mental breakdown that ends in insanity. Its first signs usually appear after the age of 50. Michael Greenberg of Children's Hospital in Boston and his colleagues looked at how a different protein, spelled huntingtin, caused the death of nerve cells growing in a test tube. They found the cells died only when the nucleus was invaded, this time by huntingtin.The findings do not mean an imminent treatment for the diseases. "But we're really beginning to understand some important aspects of the cell biology of this disease,'' said Orr, whose genetic engineering techniques blocked the development of ataxia in the mice. The next step is to try to do the same thing with a drug,'' he said. "We know how. We just need a specific agent.''
Body's defence system to be given a wake-up call A MOLECULE designed to repair defective genes in people with inherited disorders is about to be tested The new gene therapy could revolutionise treatment for
conditions as diverse as haemophilia, cystic fibrosis, and muscular dystrophy.
Instead of trying to replace defective genes, as existing therapy does, the new
technology centres on giving a "wake-up call" to the body's own
cell-repair system by spotlighting the mutation. A number of gene-therapy techniques have been tried. Most use empty viral cells to try to deliver correct genes or segments of genes to right the defect. Although a small number of operations have been carried out over the past decade, none is yet considered clinically viable. Dr Michael Blaese, chief scientist at the American biotech company Kimeragen which was set up to develop the new technology, says gene repair has huge potential. "It has immense implications," says Blaese, a paediatrician and geneticist who carried out the world's first gene-therapy procedure on a patient nearly 10 years ago. "As a geneticist and paediatrician I saw terrible genetic conditions and it was very frustrating because traditional gene therapy, where you package genes into viruses, was simply not allowing us to treat most inherited diseases. I'm very excited about this new approach - it's a quantum advance."At the heart of the new approach are molecules that are hybrids of DNA and its chemical cousin, RNA. Known as chimeras, these molecules are designed to trigger the body's own repair system to make good the genetic defect. Cells do not correct mutations naturally - they are unable to recognise a defect because there is no perfect template for a comparison. The chimera molecule provides the repair system with a template so mutations can be corrected. The molecule is made up of a double strand of DNA, which includes two lengths of RNA. Between these two stretches of RNA is a small piece of DNA that is the correct code for the area of the DNA that is mutated in the patient's own genetic material.When the molecules get into the cells, the two lengths of RNA bind tightly to the parts of the DNA of the cell to which they correspond. With the RNA firmly in place, the short section of correct DNA between them, which carries the correct genetic code, is held against the area of the mutation. The cell-repair system is then able to spot the mismatch and recognise there is a defect in the DNA that needs correcting. Using the imported short section of DNA as a template, it changes its own DNA to match the correct sequence. The chimera molecules degrade and disappear in a short time.So far the technique has been successfully tested on bacteria, yeast, insects, plants, animals and human cells in culture. In tests with rats, 40% of liver cells were changed by the molecules. The next step is a clinical trial, which is expected to start within months and will at first involve three patients with a rare inherited genetic kidney disorder called Crigler-Najjar disease.It is expected that patients will be injected with the molecules, which will be taken up by the liver from where they make their way to the nucleus of the cells to deliver their wake-up call.
Bird brains may help humans
The work raises the possibility that people whose brains have been damaged by stroke, Alzheimer's or other degenerative diseases could be helped to grow new ones. Canaries inspired the research because, the scientists found, every year the cells that control their song die off to be replaced by new ones the following spring. This suggested that their brains contained a growth factor that might exist, dormant, in other species. Researchers in America have experimented on other bird species by destroying the cells that govern song, and say they have found the molecules that can rebuild them. "This is early work and it will be years and possibly decades before it leads to treatment for human diseases," said Professor Jeffrey Macklis, a neurologist at Harvard University. The research will be published shortly and until then the details are secret. Human brain cells do not divide and grow after childhood. Even if they could, they would have to grow in exactly the right direction and form the same connections to other cells as their dead predecessors. Since nerve cells function through "axons" extending across the brain, regrowing them was seen as impossible. The Harvard research suggests it may not be. There have been similar successes in mice, which as mammals are closer to humans. The team found that if a damaged mouse brain was injected with foetal cells and drugs, they could reactivate the genes that make the brain grow in the foetal stage. In particular, they could switch on the cells that build the fine scaffolding that nerve cells traverse as they grow to connect different areas. "Our goal is the reconstruction of brain circuitry at the cellular level," said Macklis. "It aims to make possible new avenues of treatment for diseases long thought impossible to repair."
Gene therapy 'can reverse muscular dystrophy'
S cientists have used gene therapy to reverse the crippling effects of muscular dystrophy in animals.A team from the Children's National Medical Center in Washington and the University of Pittsburgh has become the first to show that whole muscles can be restored to full fitness using gene therapy. They presented their findings to the annual meeting of the American Society of Human Genetics in San Francisco on Friday. Researcher Devin Dressman said: "We are very excited by these preliminary results, which suggest that we can use a non-toxic virus to safely shuttle a gene for an important muscle protein that is improperly made in people suffering limb girdle muscular dystrophy. "These findings demonstrate the feasibility of using the gene therapy approach in treating affected patients." In their experiments, the investigators used a non-replicating adeno-associated virus (AAV) to carry a gene that stimulates production of the sarcoglycan protein, an important constituent of skeletal muscle. AAV is ideal for the task because it does not provoke an immune response from the body.
The AAV-sarcoglycan gene combination was injected into the leg muscles of a hamster with limb girdle muscular dystrophy. One month later the muscles had increased by nearly 100% in strength and had resumed normal size. Limb girdle muscular dystrophy causes rapid degeneration of the large muscles attached to the shoulders and hips. There is no current cure, and the disease is fatal. The researchers hope that their technique can be modified to treat other common forms of muscular dystrophy, such as the lethal condition, Duchenne muscular dystrophy. THAT'S ALL FOLKS!
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SCIENTISTS
researching canary's brains may have thrown 100 years of neuroscience into
disarray,
