Lab work raises potential for gene therapy breakthrough in Down syndrome

Date: Jul-18-2013A first step toward chromosome treatment for Down sydrome, also known as trisomy 21, was revealed this week when a
Nature study published online Wednesday described how a US team used a naturally occurring genetic technique to silence
the extra chromosome responsible for the genetic disorder.

Down syndrome occurs when instead of having 23 pairs of chromosomes, including a pair of sex chromosomes, the affected
individual has three copies of chromosome 21.

This "trisomy 21" causes learning difficulties, and many physical health
disadvantages, including heart defects, greater risk for childhood leukemia, disrupted immune and endocrine systems, and early
development of Alzheimer's disease.

In their proof of principle study, senior author Jeanne Lawrence, professor of cell and developmental biology at University of
Massachusetts Medical School (UMASS), and colleagues show for the first time how the genetic alteration underlying Down syndrome
can be suppressed in test tube cells.

The study is a breakthrough because while lots of studies have shown how it is possible to correct a single gene, nobody else has
done this to a whole chromosome, never mind one in a trisomic cell.

By taking this step, the researchers have offered a starting point for studying how the disorder affects other parts of the
genome. For example, which pathways may be involved? How are the genetics and associated biology that underlie the syndrome affected
by the presence or absence of this extra chromosome?

Knowing this has not been possible before. The results of such investigations could one day provide new targets for drugs and gene
therapies.
Past, present and future progress for single-gene disorders

Lawrence says in a statement that the last ten years have seen huge progress in ability to correct single-gene disorders. These
projects started with test tube cells, moved to live cells, and now some are at the clinical trial stage.
Jeanne Lawrence explains:

"By contrast, genetic correction of hundreds of genes across an entire extra chromosome has remained outside the realm of
possibility.

Stem-cell researcher Nissim Benvenisty of Hebrew University in Jerusalem says in a Nature News report on the study that
for researchers working on Down syndrome, "the idea of shutting off a whole chromosome is extremely interesting."

He anticipates future studies will compare cells with chromosome 21 switched on to cells with it switched off, in order to see how they
differ in function and response to treatment.

For their study, the researchers harnessed the power of an RNA gene called XIST, which normally silences one of the two X
chromosomes in female mammals.

They found using patient-derived stem cells in the lab, they could get XIST to silence other chromosomes as well, including the extra
copy of chromosome 21 in cells from people with Down syndrome.

The method relies on the fact XIST effectively "paints" over the extra chromosome so its DNA cannot be expressed to produce
proteins and other components. The chromosome is not removed, but simply deactivated, along with most of its genes.

The ability to turn XIST on and off offers a chance to study a "host of different questions," says
Lawrence.

"We now have a powerful tool for identifying and studying the cellular pathologies and pathways impacted directly due to over-expression of chromosome 21," she adds.

The team now plans to see if the new tool can correct chromosome defects in mouse models of Down syndrome.

In a study published earlier this year, another team of scientists described how they found certain second trimester markers for Down syndrome that are identified
in an ultrasound are more significant than others.
Written by Catharine Paddock PhD

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