Engineering a cure

By Nell Boyce in Washington DC THE first trial to test whether gene therapy can slow the progress of Alzheimer’s disease has been given the go-ahead. In theory the same technique could be used to enhance the cognitive ability of people who aren’t suffering from dementia. Alzheimer’s is the most common cause of dementia in older people, killing brain cells called cholinergic neurons. As the number of elderly people in developed nations increases, it is exacting an ever more devastating toll (see Figure), so finding effective ways to treat it is a top priority. Researchers led by Mark Tuszynski of the University of California, San Diego, are betting that a substance called nerve growth factor (NGF) will stave off dementia not only by preventing the death of cholinergenic neurons, but also by promoting new connections between the cells. A decade of experiments on rodents and primates shows that NGF helps protect cholinergic neurons and can reverse memory loss. In September, for instance, Tuszynski’s team showed that NGF gene therapy could reverse age-related neural degeneration in rhesus monkeys, with the genes remaining active for at least a year (New Scientist, 18 September, p 6). Shortly before Christmas, the National Institutes of Health’s Recombinant DNA Advisory Committee (RAC) cleared an initial safety study that will involve eight people with early Alzheimer’s disease who can understand and consent to the procedure. First, the researchers will take cells called fibroblasts from the patients’ skin and genetically engineer them to produce NGF by adding extra copies of the gene using a mouse leukaemia virus modified to ensure that it shouldn’t trigger cancer. Then they will inject the NGF-producing cells into the base of the patients’ forebrains. Although the RAC agreed that the virus that will be used to deliver the NGF gene poses little risk, one member did question the growth factor itself. Wilma Friedman of Columbia University in New York noted that NGF can kill brain cells that carry a receptor called p75 but not another called trk. However, Tuszynski points out that cells in the basal forebrain seem to have both receptors. The main goal of the trial is to assess the maximum dose of modified cells that can be safely injected. But Tuszynski will also look to see if the disease progresses more slowly than normal. “We think there is a direct potential for benefit,” he says. The researchers have had to resort to gene therapy because NGF injected into the blood stream doesn’t readily cross the blood-brain barrier. However, any genetic technique that affects brain function has the potential to generate controversy. Earlier this year, for instance, when Joe Tsien and his colleagues at Princeton University in New Jersey created transgenic mice with improved memories by boosting levels of the gene for a receptor on the surface of brain cells called NMDA, there was widespread speculation about using the human version of the gene to engineer “supersmart” people (New Scientist, 4 September, p 15). Tuszynski plays down these fears. “Most of these studies that demonstrate enhanced brain function with growth factors or other agents, like Tsien’s, have been done to understand what the normal, physiological role of a gene is,” he says. Using similar techniques to treat debilitating diseases such as Alzheimer’s doesn’t mean that anyone is suggesting that they should be used to improve normal human cognitive function, Tuszynski stresses. However, Eric Juengst, a bioethicist at Case Western Reserve University in Cleveland, says that many gene therapies designed to treat disease also have potential for genetically enhancing healthy people. “This just highlights a problem that the RAC will see increasingly,
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