Scientists silenced the extra copy of a chromosome that causes Down syndrome in laboratory stem cells, offering the first evidence that it may be possible to correct the genes responsible for the disorder.
The findings, published Wednesday in the journal Nature, offer new cell models for developing potential treatments, researchers said. The models, aided by gene-manipulating technology from Sangamo Biosciences Inc., may help researchers discover drug targets for other ill health effects that come with the syndrome, including heart disease, hearing difficulties, and weakened muscles.
Down syndrome slows physical and intellectual development. About 6,000 babies are born every year with the condition, which is caused by an extra copy of chromosome 21, according to the U.S. Centers for Disease Control and Prevention. While some genetic disorders have been easier to study because a single gene drives them, Down syndrome is more complex, said Robert Nussbaum, chief of genomic medicine at the University of California, San Francisco.
"It's a technical tour-de-force," Nussbaum said of the research, in a telephone interview. "We don't really understand why the extra copy of chromosome 21 causes the problems it does. So this might allow us to have a thorough description of what goes wrong." Nussbaum wasn't involved in the study.
While the findings aren't a cure for Down syndrome, they make what was once a mysterious disorder much easier to study, Nussbaum said.
In Wednesday's paper, researchers led by Jeanne Lawrence, a professor of the department of cell and developmental biology at the University of Massachusetts Medical School, used a gene called Xist. The gene creates a regulating piece of RNA that ordinarily quiets the second X chromosome in women. In women, the extra RNA makes copies that coat the whole second X chromosome, preventing it from producing proteins. The scientists wondered if this quieting effect could be used specifically to silence the third copy of chromosome 21.
The scientists used skin cells from a Down syndrome patient that had been tricked into reverting into stem cells that, like embryonic ones, can grow into any type of tissue. Then they inserted a copy of Xist into the extra chromosome using technology from Richmond, California-based Sangamo.
Once inserted into the stem cells, scientists switched on Xist using the antibiotic tetracycline, setting off a process that effectively silenced the extra chromosome, Lawrence said.
When the chromosome had been silenced, the cells grew better in the culture, Lawrence said. What's more, they saw an increased rate of formation of cells that are precursors to neurons.
The most immediate application for the discovery is to learn about how the extra chromosome affects the development of cells, said Lawrence.
"We do hope that over the longer term, the idea of chromosome therapy could be applied to some aspects of the disease," she said. That's more than a decade away, she said. Because the technique wouldn't work in all the cells of the body, gene therapy based on this work could only be used for targeted effects, such as lowering the risk of blood cancers. Even a gene therapy for Down syndrome wouldn't necessarily be a cure, she said.
Physical issues that accompany Down syndrome include heart defects, stomach trouble, hearing difficulties and a higher likelihood of childhood leukemia. Alzheimer's disease is also very common among patients with the disorder. About 80 percent of people with Down syndrome acquire the dementia, due to the extra copy of a gene that boosts the formation of characteristics of Alzheimer's plaques in the brain.
"Down syndrome is underfunded," Lawrence said. "We're hoping what we've done here will accelerate multiple avenues of research, and maybe give more hope to the community."
Philip Gregory, the chief scientific officer of Sangamo, said the company plans to continue working with Lawrence's group. He declined to say whether Sangamo would have any special rights over discoveries made using the technique.
While women who are 35 and older have a higher risk of giving birth to babies with Down syndrome, about 80 percent of babies with the disorder are born to women who are younger than that, according to the CDC. The error that causes Down syndrome occurs when either the sperm or egg is formed by the parents, so that the baby ends up with 47, rather than 46, chromosomes in every cell of the body. Why these errors happen isn't known.
The average life expectancy of a person with Down syndrome is 55 years, according to the National Association for Down Syndrome, an advocacy organization, though some people live longer.