Compound Found to Reverse Down Syndrome-Like Learning Deficits in Mice

They reported that the single-dose treatment appears to enable the cerebellum of the rodents’ brains to grow to a normal size.

The scientists cautioned that use of the compound, a small molecule known as a sonic hedgehog pathway agonist, has not been shown to be safe to try in individuals with Down syndrome, but say their research has potential for developing similar drug.

The study’s findings were published in the September 4, 2012, issue of the journal Science Translational Medicine. “Most people with Down syndrome have a cerebellum that’s about 60% of the normal size,” stated Roger Reeves, PhD, a professor in the McKusick-Nathans Institute of Genetic Medicine at the Johns Hopkins University School of Medicine (Baltimore, MD, USA). “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.”

Dr. Reeves has spent his career studying Down syndrome, a disorder that occurs when people have three, instead of the typical two, copies of chromosome 21. As a result of this trisomy, individuals 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. Because the disorder involves so many genes, developing therapy for it is a daunting task, according to Dr. Reeves.

Dr. Reeves and his colleagues, for the current research 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 features similar to those of people with Down syndrome, including comparatively small cerebellums and difficulty learning and remembering how to navigate through a recognizable space. (In the case of the mice, this was evaluated by tracking how easily the animals located a platform while swimming in a so-called water maze.)

Based on earlier research on how Down syndrome affects brain development, the researchers tried supercharging a biochemical chain of events known as the sonic hedgehog pathway that stimulate growth and development. They used an agent—a sonic hedgehog pathway agonist—that could accomplish the feat. 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,” Dr. Reeves noted.

However, the researcher went beyond measuring the cerebellums, also looking for changes in behavior. “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,” Dr. Reeves said. The scientists assessed the treated mice against untreated Down syndrome-like mice and healthy mice in a host of ways, and found that the treated mice did just as well as the normal ones on the water maze test.

Dr. Reeves noted that additional studies are needed to learn why exactly the treatment works, because their study of specific cells in the hippocampus known to be involved in learning and affected by Down syndrome appeared unaffected by the sonic hedgehog agonist treatment. One idea is that the treatment improved learning by strengthening communication between the cerebellum and the hippocampus, he noted.

As for the agent’s potential to become a drug for human use, the difficulty, according to Dr. Reeves, is that changing an important biologic chain of events such as sonic hedgehog would in all probability have many unintended effects throughout the body, such as increasing the risk of cancer by triggering uncontrolled growth. But now that the investigators have seen the potential of this approach, they will look for more targeted ways to safely control the power of sonic hedgehog in the cerebellum. Even if his team succeeds in developing a clinically useful drug, however, Dr. Reeves warned that it would not represent 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 concluded. “Multiple approaches will be needed.”

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Johns Hopkins University School of Medicine