Silencing extra chromosome could yield Down syndrome treatments

By Andrew Porterfield

Down syndrome, or Trisomy 21, is the world's most common chromosome disorder. About one in every 691 births carries the extra 21st chromosome that causes Down syndrome. So far, such extra-chromosomal disorders have no treatment or prevention. But Massachusetts researchers have found a possible way to correcting the genetic disorder--just shut down the extra chromosome.

In a paper in Nature, Jeanne Lawrence, a biologist at the University of Massachusetts Medical School, and her team found that by using the same molecule that keeps females from over-expression of their extra "X" chromosome, they could shut down the expression of genes on the extra 21st chromosome carried by people with Down syndrome.

Gene therapy or prevention of the disorder would depend on the ability to identify and shut down specific genetic pathways and mechanisms started by the presence of the extra chromosome. The molecule used for shutting down chromosomes, an RNA molecule called XIST, is effective at shutting down similar pathways on the human X chromosome, which then prevents genetic disorders in women (who carry two X chromosomes).

"The last decade has seen great advances in efforts to correct single-gene disorders," said Lawrence. "By contrast, genetic correction of hundreds of genes across an entire extra chromosome has remained outside the realm of possibility." Learning exactly which genetic pathways can be shut down or altered could then pave the way to a new type of chromosome therapy. However, it is not yet known exactly what genetic pathways are altered by the extra 21st chromosome, and it further isn't known whether shutting down the extra chromosome could cause harm elsewhere in the genome.

The researchers first found a way to insert the X chromosome's XIST molecule into one copy of chromosome 21. XIST works not by coding for a protein itself (a normal part of gene expression), but instead by regulating the actions of other genes. By inserting XIST in induced adult stem cells of patients with Down Syndrome, they were able to see the effects of shutting down the chromosome in cells. XIST modifies chromosome structure so that its DNA can't be expressed anymore, rendering most of the genes on the chromosome inactive.

The key issue with using chromosome therapy, however, is the word "most." Not all genes are silenced by XIST, either on the X chromosome or in Lawrence's experiments with trisomy 21. Knowing whether those un-silenced genes contribute to disease (or conversely, whether silenced genes may help stem it) will be another important step before any clinical treatments are available. Down syndrome, in fact, has very variable symptoms, indicating that the three 21st chromosomes may be working very differently between patients with the disease.

"We now have a powerful tool for identifying and studying the cellular pathologies and pathways impacted directly due to over-expression of chromosome 21," Lawrence said. Her team is now studying the use of XIST and "chromosome therapy" in mouse models of Down syndrome.


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