New drugs may transform Down syndrome

Recent breakthroughs could lead to pharmacological treatments for the chromosomal disorder

Jenni Laidman, Scientific American

Topics: Scientific American, down syndrome, Drugs, Pharmaceuticals, John Hopkins University, neurology, Innovation News, Life News

This article was originally published by Scientific American.

People born with Down syndrome have always been considered to be incurably developmentally delayed—until now. In the past few years a number of laboratories have uncovered critical drug targets within disabled chemical pathways in the brain that might be restored with medication. At least two clinical trials are currently studying the effects of such treatments on people with Down syndrome. Now geneticist Roger Reeves of Johns Hopkins University may have stumbled on another drug target—this one with the potential to correct the learning and memory deficits so central to the condition.

Down syndrome occurs in about one in 1,000 births annually worldwide. It arises from an extra copy of chromosome 21 and the overexpression of each of the 300 to 500 genes the chromosome carries. “If you go back even as recently as 2004, researchers didn’t have much of a clue about the mechanisms involved in this developmental disability,” says Michael Harpold, chief scientific officer with the Down Syndrome Research and Treatment Foundation. But all that has changed. “In the past six or seven years there have been several breakthroughs—and ‘breakthroughs’ is not by any means too big a word—in understanding the neurochemistry in Down syndrome,” Reeves says.

This improved knowledge base has led to a series of discoveries with therapeutic promise, including the latest by Reeves. He and his team were attempting to restore the size of the cerebellum in mice engineered to show the hallmarks of Down syndrome. The cerebellum lies at the base of the brain and controls motor functions, motor learning and balance. In people with Down syndrome and in the Down mouse model the cerebellum is about 40 percent smaller than normal. By restoring its size, Reeves hoped to gain a clearer picture of the developmental processes that lead to anomalies in a brain with Down syndrome.

Reeves’s team injected newborn Down mice with a chemical that stimulates an important neurodevelopmental pathway that, among other things, orchestrates cerebellum growth. “We were not in fact surprised that we fixed the cerebellum. That was our working hypothesis,” Reeves says. Yet he had not anticipated that three months after treatment the mice with a restored cerebellum would be able to learn their way around a water maze—a function of learning and memory thought to be controlled by another part of the brain, the hippocampus. The researchers do not yet know whether they inadvertently repaired the hippocampus or whether the cerebellum might be responsible for more learning and memory functions than previously realized.

In fact, other investigational treatments for Down syndrome target the hippocampus—but none target this particular chemical pathway. Reeves’s study, published recently in Science Translational Medicine, may point to a pharmaceutical intervention that could allow those with Down syndrome to live more independent lives. “The possibility of actually giving Down syndrome people the ability to improve learning and memory significantly—that’s something I never thought I’d see in my entire career,” he says. “And it’s now happening. The game has changed.

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