Switching off the Down's syndrome genes

The big science story of the week is undoubtably the remarkable results from US researchers who have successfully silenced the extra chromosome responsible for Down’s syndrome.

The scientists, who published their results in Nature,  took cells from people with Down’s and were able to silence the extra chromosome 21 responsible for the traits that lead to Down’s Syndrome, which leads to learning and developmental problems and longterm physical problems too.

Here’s how the Guardian described it:

Lawrence’s team used “genome editing”, a procedure that allows DNA to be cut and pasted, to drop a gene called XIST into the extra chromosome in cells taken from people with Down’s syndrome.

Once in place, the gene caused a buildup of a version of a molecule called RNA, which coated the extra chromosome and ultimately shut it down.

Scientists stress that a chromosome therapy to prevent Down’s syndrome is probably over a decade away, but this is an important step in making it a reality. Next step for the scientists is attempting the gene treatment in mice.

Down’s syndrome affects one baby in 1000 born, according to the New Zealand Down Syndrome Association.

My colleagues at the Science Media Centre in London gathered reaction from UK-based scientists. Here’s what they had to say:

Professor Neil Brockdorff, Professor of Developmental Epigenetics, University of Oxford, said:

“Having three rather than the usual two copies of chromosome 21 results in Down’s syndrome, highlighting that normal embryonic development requires not just the correct genes but also the correct level of genes.  Another example where gene levels are important occurs in female mammals where one of the two X chromosomes is genetically inactivated in order to balance the level of X-linked genes relative to males that have only a single X chromosome. This natural process, termed X inactivation, is controlled by a single master regulator gene, termed Xist (X inactive specific transcript), that functions to silence the majority of genes on the chromosome on which it resides. In this study researchers have harnessed the ability of the Xist gene to silence an entire chromosome in order to correct chromosome 21 imbalance in induced pluripotent stem (iPS) cells obtained from Down’s syndrome patients.  A copy of the Xist gene was inserted into one copy of chromosome 21 present in the patient derived cells and was then induced to silence all of the genes on that single chromosome 21 copy. The resulting cells had corrected chromosome 21 gene levels and moreover could maintain this state for several cell generations after removal of the original inducing signal.

“This study represents an innovative application of genetic technology and an important advance in efforts to understand the basic biology of Down’s syndrome.  The iPS cells that have been derived can for example be used to test whether restoration of correct gene levels in specific cell types can reverse deficiencies that are linked to Down’s syndrome.  In the long term it may even be possible to make the correction in patient specific cell lines, and then use these for cell therapy, treating specific problems that individuals experience.  However, the breakthrough shouldn’t be viewed as heralding a cure for Down’s syndrome.  This is because Down’s is a sporadic disorder that affects normal development of several tissues of the foetus.  There is no way of knowing in advance which embryos could be affected, and by the time diagnosis has been made, it wouldn’t be possible to intervene in a holistic sense, correcting the genetic imbalance in all cells of the foetus or newborn child.  It is worth considering that Down’s syndrome patients and their families may argue that there is no need for a cure. Affected individuals generally have a good quality of life, reasonable longevity and are nearly always treasured and very loved members of their families.”

Dr Lucy Raymond, Reader in Neurogenetics and Honorary Consultant in Medical Genetics, University of Cambridge, said:

“This new study has used a very neat and elegant experimental model to demonstrate that the natural mechanism of counting chromosomes, that exists on our X sex chromosome in all our cells, can be cut-and-pasted onto a copy of chromosome 21, therefore silencing this extra copy and effectively leaving the normal complement of two functioning copies of chromosome 21 in a cell.  The counting mechanism exists naturally on X chromosomes so that in female mammals one copy of the X chromosome (females have two Xs and males have one X and one Y) is silenced so males and females have the same number of working copies of the X chromosome gene products.  This group have demonstrated an important proof of concept – that this mechanism can be experimentally harnessed and successfully silences a non-sex chromosome (in this case chromosome 21, an extra copy of which leads to Down’s syndrome in humans).

“This is an exciting breakthrough, but this process is still at a very early (cellular) stage and we are nowhere near seeing this procedure being used in the treatment of Down’s syndrome in people.

“This new study could, however, lead to extremely useful further studies looking at which particular genes on chromosome 21 cause certain aspects of Down’s syndrome, and which might therefore be good targets for therapeutic agents.”

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