Lab experiment reverses Down syndrome in mice 
 
 (AFP) – Sep 4, 2013 
 
 WASHINGTON — US researchers said Wednesday they have found a way to reverse Down syndrome in newborn lab mice by injecting an experimental compound that causes the brain to grow normally. 
 
 While the study in the journal Science Translational Medicine offers no direct link to a treatment for humans, researchers are hopeful it may someday offer a path toward future breakthroughs. 
 
 There is no cure for Down syndrome, which is caused by the presence of an additional chromosome, leading to extra copies of more than 300 genes and causing intellectual disabilities, distinctive facial features and sometimes other health problems. 
 
 The team at Johns Hopkins University used lab mice that were genetically engineered to have extra copies of about half the genes found on human chromosome 21, leading to Down syndrome-like conditions such as smaller brains and difficulty learning to navigate a maze. 
 
 On the day the mice were born, scientists injected them with a small molecule known as a sonic hedgehog pathway agonist. 
 
 The compound, which has not been proven safe for use in human, is designed to boost normal growth of the brain and body via a gene known as SHH. 
 
 The gene provides instructions for making a protein called sonic hedgehog, which is essential for development. 
 
 "It worked beautifully," said lead author Roger Reeves of the Johns Hopkins University School of Medicine. 
 
 "Most people with Down syndrome have a cerebellum that's about 60 percent of the normal size," he said. 
 
 "We were able to completely normalize growth of the cerebellum through adulthood with that single injection." 
 
 The injection also led to unexpected benefits in learning and memory, normally handled by a different part of the brain known as the hippocampus. 
 
 Researchers found that the treated mice did as well as normal mice on a test of locating a water platform while in a swimming maze. 
 
 However, adjusting the treatment for human use would be complicated, since altering the growth of the brain could lead to unintended consequences, like triggering cancer. 
 
 "Down syndrome is very complex, and nobody thinks there's going to be a silver bullet that normalizes cognition," he said. "Multiple approaches will be needed." 
 
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 Citations Science Translational Medicine; R01 HD38384; MH51106; R01 NS39156 
 
 Newswise — Researchers at Johns Hopkins and the National Institutes of Health have identified a compound that dramatically bolsters learning and memory when given to mice with a Down syndrome-like condition on the day of birth. As they report in the Sept. 4 issue of Science Translational Medicine, the single-dose treatment appears to enable the cerebellum of the rodents’ brains to grow to a normal size. 
 
 The scientists caution that use of the compound, a small molecule known as a sonic hedgehog pathway agonist, has not been proven safe to try in people with Down syndrome, but say their experiments hold promise for developing drugs like it. 
 
 “Most people with Down syndrome have a cerebellum that’s about 60 percent of the normal size,” says Roger Reeves, Ph.D., a professor in the McKusick-Nathans Institute of Genetic Medicine at the Johns Hopkins University School of Medicine. “We treated the Down syndrome-like mice with a compound we thought might normalize the cerebellum’s growth, and it worked beautifully. What we didn’t expect were the effects on learning and memory, which are generally controlled by the hippocampus, not the cerebellum.” 
 
 Reeves has devoted his career to studying Down syndrome, a condition that occurs when people have three, rather than the usual two, copies of chromosome 21. As a result of this “trisomy,” people with Down syndrome have extra copies of the more than 300 genes housed on that chromosome, which leads to intellectual disabilities, distinctive facial features and sometimes heart problems and other health effects. Since the condition involves so many genes, developing treatments for it is a formidable challenge, Reeves says. 
 
 For the current experiments, Reeves and his colleagues used mice that were genetically engineered to have extra copies of about half of the genes found on human chromosome 21. 
 
 The mice have many characteristics similar to those of people with Down syndrome, including relatively small cerebellums and difficulty learning and remembering how to navigate through a familiar space. (In the case of the mice, this was tested by tracking how readily the animals located a platform while swimming in a so-called water maze.) 
 
 Based on previous experiments on how Down syndrome affects brain development, the researchers tried supercharging a biochemical chain of events known as the sonic hedgehog pathway that triggers growth and development. They used a compound — a sonic hedgehog pathway agonist — that could do just that. 
 
 The compound was injected into the Down syndrome-like mice just once, on the day of birth, while their cerebellums were still developing. “We were able to completely normalize growth of the cerebellum through adulthood with that single injection,” Reeves says. 
 
 But the research team went beyond measuring the cerebellums, looking for changes in behavior, too. “Making the animals, synthesizing the compound and guessing the right dose were so difficult and time-consuming that we wanted to get as much data out of the experiment as we could,” Reeves says. The team tested the treated mice against untreated Down syndrome-like mice and normal mice in a variety of ways, and found that the treated mice did just as well as the normal ones on the water maze test. 
 
 Reeves says further research is needed to learn why exactly the treatment works, because their examination of certain cells in the hippocampus known to be involved in learning and affected by Down syndrome appeared unchanged by the sonic hedgehog agonist treatment. One idea is that the treatment improved learning by strengthening communication between the cerebellum and the hippocampus, he says. 
 
 As for the compound’s potential to become a human drug, the problem, Reeves says, is that altering an important biological chain of events like sonic hedgehog would likely have many unintended effects throughout the body, such as raising the risk of cancer by triggering inappropriate growth. But now that the team has seen the potential of this strategy, they will look for more targeted ways to safely harness the power of sonic hedgehog in the cerebellum. Even if his team succeeds in developing a clinically useful drug, however, Reeves cautions that it wouldn’t constitute a “cure” for the learning and memory-related effects of Down syndrome. “Down syndrome is very complex, and nobody thinks there’s going to be a silver bullet that normalizes cognition,” he says. “Multiple approaches will be needed.” 
 
 Other authors on the paper were Jung H. Shin of the National Institute on Alcohol Abuse and Alcoholism, and Ishita Das, Joo-Min Park, Soo Kyeong Jeon, Hernan Lorenzi, David J. Linden and Paul F. Worley, all of the Johns Hopkins University School of Medicine. 
 
 The study was funded by the Down Syndrome Research and Treatment Foundation, Research Down Syndrome, the National Institute of Child Health and Human Development (grant number R01 HD38384), the intramural programs of the National Institute on Alcohol Abuse and Alcoholism, the National Institute of Mental Health (grant number MH51106) and the National Institute of Neurological Disorders and Stroke (grant number R01 NS39156). 
 
 
 
 Comment/Share ||||| Scientists have taken another step forward when it comes to treating Down syndrome. They've discovered a compound that dramatically bolsters learning and memory in mice that have had Down syndrome-like symptoms since birth. This "reversal" of the syndrome could help with future research. (Photo : Reuters) 
 
 Scientists have taken another step forward when it comes to treating Down syndrome. They've discovered a compound that dramatically bolsters learning and memory in mice that have had Down syndrome-like symptoms since birth. This "reversal" of the syndrome could help with future research. 
 
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 Down syndrome is a condition that occurs when people have three, rather than the usual two, copies of chromosome 21. As a result of this, people with Down syndrome have extra copies of the more than 300 genes that are housed on that chromosome. This, in turn, leads to intellectual disabilities, distinctive facial features and sometimes heart problems and other health effects. 
 
 The compound is a small molecule known as a sonic hedgehog pathway agonist. Currently, it has not been proven safe to try in people with Down syndrome. Yet this latest discovery does hold promise for developing drugs like it. 
 
 "Most people with Down syndrome have a cerebellum that's about 60 percent of the normal size," said Roger Reeves, one of the researchers, in a news release. "We treated the Down syndrome-like mice with a compound we thought might normalize the cerebellum's growth, and it worked beautifully. What we didn't expect were the effects on learning and memory, which are generally controlled by the hippocampus, not the cerebellum." 
 
 In the experiment, the researchers used mice that were genetically engineered to have extra copies of about half of the genes found on human chromosome 21. This causes the mice to have many characteristics similar to people with Down syndrome. The scientists injected the compound into the Down syndrome-like mice just once on the day of their birth while their cerebellums were still developing. They then tested the treated mice against untreated Down syndrome-like mice and normal mice. 
 
 It turned out that the treated mice performed just as well as normal mice in tests. This is a huge step toward potentially developing drugs for human use. Currently, the researchers plan to conduct more research to find out exactly why the treatment works. Yet the scientists remain cautious. 
 
 "Down syndrome is very complex, and nobody thinks there's going to be a silver bullet that normalizes people," said Reeves. "Multiple approaches will be needed." 
 
 The findings are published in the journal Science Translational Medicine.
– We'll start by tempering expectations: The breakthrough you're about to read about has "no direct link" to a human treatment, reports AFP, but it's noteworthy nonetheless. Scientists say they've identified a molecule that "reverses" the effects of Down syndrome in mice. The molecule is called sonic hedgehog pathway agonist, and it was administered to mice who were genetically altered to have characteristics akin to those of Down syndrome. The molecule, which is not approved as safe for humans, spurs a gene to make a protein tied to development. "Most people with Down syndrome have a cerebellum that's about 60% of the normal size," says one of the Johns Hopkins researchers. Science World Report notes that the mice were injected on the day they were born, at which point their cerebellums hadn't fully developed. The single injection appeared to normalize the cerebellum's growth. In an added surprise, memory and learning, "which are generally controlled by the hippocampus, not the cerebellum," were also positively affected. But the researcher explains that applying the treatment to humans is a tricky proposition, and could have unintended consequences, like raising cancer risk.