Breakthrough in Parkinson’s gene therapy(帕金森基因疗法取得突破)
The world’s first gene therapy for a brain disease brought about significant improvements in the mobility of Parkinson’s sufferers. American doctors said it could also herald a landmark in the treatment of other neurological disorders, such as Alzheimer’s or epilepsy but there was a lingering doubt that the reports by a dozen patients of improvements of up to 65 per cent in mobility could be anecdotal or due to the placebo effect.
Today, Prof David Eidelberg of the of The Feinstein Institute for Medical Research in Manhasset, New York, and colleagues report in the Proceedings of the National Academy of Sciences evidence that the brain chemistry of the patients has been altered by gene therapy, ending concerns that the evidence that it worked depended too much on what the patients said and not enough on objective measures. ”It is the first solid evidence of benefit from gene therapy. It is objective,” Prof Eidelberg told The Daily Telegraph.
Parkinson’s affects about 120,000 people in Britain, with 10,000 new cases diagnosed every year. It robs sufferers of the ability to walk and even eat, causes long motionless periods known as ”freezing” as well as head and limb tremors. As the disease progresses, higher doses of drugs are required, leading to side-effects that include involuntary movements.
Sufferers include the former world boxing champion Muhammad Ali and the actor Michael J Fox.
The research team, from the New York-Presbyterian Hospital/Weill Cornell Medical Centre and the New Jersey-based company Neurologix, used the gene therapy to fix some of the damage caused by the disease.
Parkinson’s occurs when the brain cells - neurons - that release the messenger chemical known as dopamine die. Protein deposits also form in the brain, and levels of another messenger chemical called GABA - which calms overexcited brain cells - drop.
The study, begun in 2003, was carried out on 11 men and one woman with an average age of 58, who had all had severe Parkinson’s for at least five years and for whom current therapies were no longer effective.
Prof Matthew During from Ohio State University grew copies of the human gene used in the therapy in bacteria from DNA isolated from a human sample and the gene multiplied with the bacteria for the treatment.
The gene was packaged in a virus and patients were given injections of billions of copies of the genetically altered viruses into part of the brain called the subthalamic nucleus. To show that the treatment was truly having an effect, and the gene was being inserted into brain cells, the doctors injected only on one side of their brains, leaving the untreated side of the brain as a control.
Scans to reveal the use of glucose in the brain to signal how active each area is, now show that changes were only significant on the treated side of the brain, said Prof Eidelberg. ”We have been able to identify very distinct metabolism in the brain of Parkinson’s patients.”
Other treatments for Parkinson’s include dopamine and deep brain stimulation with ultrafine electrodes ”reduced significiantly” these activities.
Gene therapy also produced a ”highly significant” reduction in this network at six and 12 months, said Prof Eidelberg. ”The unoperated side showed an increase and the treated sign showed a decline. And the amount of correction we saw on the scans correlated with the observed clinical improvement.”
The researchers are about to start a larger Phase 2 study in Parkinson’s disease this year and a preliminary trial with epilepsy sufferers. The success of this trial lays the foundation for the use of gene therapy against neurological diseases generally, notably Alzheimer’s and epilepsy.
Nathan Klein, 59, the first to undergo the pioneering treatment told The Daily Telegraph that before the gene therapy, he had been ”in a state that nobody could survive”.
Four years ago, Klein had a shuffling gait and tremors that could not be quashed by conventional treatments. Then Dr Michael Kaplitt inserted through the hole in his skull a fine eight inch hypodermic and injected 3.5 billion genetically altered viruses to help correct the chemical imbalance that sparks Parkinson’s.
The television producer told The Daily Telegraph that he was conscious during the five hour operation and ”told them dirty jokes.”
”Nothing happened for the first week. And then nothing happened for the second week. And then a month, and two months, and then at three months I thought I was a little better, nothing much,” Klein said. ”It was like watching grass grow. But about six months later, I started feeling a lot better.”
”This is an encouraging initial study with this technique,” commented Prof Carl Clarke of the University of Birmingham. ”However, much larger and longer clinical trials will be required before we can conclude that this treatment is both effective and safe. We are well aware of the large placebo effect in Parkinson’s disease clinical trials.
”We have also seen encouraging results in small surgery trials with foetal nigral transplants and glial-derived nerve growth factor (GDNF) reversed in larger trials leading to further development being abandoned. It will take clinical trials over the next 5 to 10 years to ensure that this technique works and that it does not harm patients. It will take even longer to establish that it is cost-effective for the NHS to fund.”
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