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article imageScientists discover how to turn off Down Syndrome chromosome

By JohnThomas Didymus     Jul 19, 2013 in Health
In a potentially revolutionary breakthrough researchers at the University of Massachusetts Medical School have demonstrated for the first time a procedure for turning off in vitro (in a laboratory dish) the extra chromosome responsible for Down Syndrome.
Down Syndrome is a genetic condition found in people with an extra copy of chromosome 21, one of the 46 chromosomes found in the cells (23 pairs of chromosomes) of normal people. It is identified as the most common chromosome abnormality in humans and is associated with cognitive disability, physical growth retardation and other health disabilities, including Alzheimer's, heart defects, immune and endocrine system disorders and leukemia.
Using stem cells from fibroblast cells donated by a Down Syndrome patient, the researchers developed a method to shut down genes on the extra chromosome 21 associated with Down Syndrome (Trisomy 21).
They achieved the feat by using an RNA gene called XIST, which is normally used to shut down the extra X chromosomes in women.
The procedure involved inserting the XIST gene into a specific location on the extra chromosome 21. XIST caused the assemblage of an RNA which shuts down the monochrome by latching on to or "coating" it.
According to the authors in a study entitled "Translating dosage compensation to trisomy 21," published in the Journal Nature on July 17, 2013, "We tested the concept that gene imbalance across an extra chromosome can be de facto corrected by manipulating a single gene, XIST (the X-inactivation gene)... we inserted a large, inducible XIST transgene into the DYRK1A locus on chromosome 21... The XIST non-coding RNA... triggers... chromosome-wide transcriptional silencing and DNA methylation to form a 'chromosome 21 Barr body.'"
The authors pointed out that their study "provides a model to study human chromosome inactivation and creates a system to investigate genomic expression changes and cellular pathologies of trisomy 21..." The also noted that "successful trisomy silencing in vitro also surmounts the major first step towards potential development of chromosome therapy."
XIST gene plays a vital role in normal embryonic development. Although it is located on the X chromosome it activated only in women where it is used to shut down the extra X chromosome by latching on to it (women have two X chromosomes while men have one X and one Y chromosome).
As Scientific American notes, the procedure that Jeanne Lawrence of the University of Massachusetts and colleagues employed mimicked a natural process for shutting down the X chromosome in the females of humans and other mammalian species.
Although the breakthrough raises for the first time the prospect of gene therapy for Down's Syndrome, the authors pointed out that a great deal of research is still needed to confirm the feasibility of the procedure for medical application.
The Guardian reports that Elizabeth Fisher, professor of neurogenetics at UCL, who was not part of the study, said: "This is a real technical breakthrough. It opens up whole new avenues of research. This is really the first sniff we've had of anything to do with gene therapy for Down's syndrome."
Lawrence told The Guardian: "This will accelerate our understanding of the cellular defects in Down's syndrome and whether they can be treated with certain drugs. The long-range possibility -- and it's an uncertain possibility -- is a chromosome therapy for Down's syndrome. But that is 10 years or more away. I don't want to get people's hopes up."
The study also opens up for the first time the possibility of gene therapy for other trisomy disorders such as Edward syndrome (trisomy 18) and Patau syndrome (trisomy 13), after the researchers found that XIST can also shut down other chromosomes too.
Brian Skotko, director of the Down Syndrome Program at Massachusetts General Hospital, who was not part of the study told The Boston Globe: "It really is revolutionary, in terms of causing us all to rethink the one impossible thought -- can you make, functionally, that extra chromosome disappear. I don’t think any of us thought it was possible or even within the current realm of scientific dreaming that we might one day be able to do it."
The Guardian reports that work has commenced already on using the procedure to treat Down's syndrome in mice. The study will explore means of silencing the extra chromosome 21 in the early-stage of embryological development in mice.
Experts note that gene therapy can be carried out for mice, but technical and ethical issues that have implications in law arise when applied to humans. Lawrence said: "That would correct the whole mouse, but it's not [yet] really practical in humans."
However, the work is already helping to shed light on how carrying an extra chromosome 21 causes the various disabilities associated with Down Syndrome. According to Fisher: "By the time people with Down syndrome are in their 60s, about 60% will succumb to dementia. One question is, if we could turn off the extra chromosome in adults, would that stop or ameliorate their dementia?"
According to CDC the disorder was found to occur in nine out of every 10,000 births in 1979, but increased to 12 out of every 10,000 births in 2003.
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