Experimental Compound Reverses Down Syndrome-Like Learning Deficits In Mice 
 
 Contact Information Available for logged-in reporters only 
 
 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. 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. 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. 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. 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. “We were able to completely normalize growth of the cerebellum through adulthood with that single injection,” 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. 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. "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.” 
 
 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.
– 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.