XIST

Researchers turn off Down’s syndrome genes.

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Silencing extra chromosome in cell cultures could lead to new treatments for the disorder.

The insertion of one gene can muzzle the extra copy of chromosome 21 that causes Down’s syndrome, according to a study published today inNature1. The method could help researchers to identify the cellular pathways behind the disorder’s symptoms, and to design targeted treatments.

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“It’s a strategy that can be applied in multiple ways, and I think can be useful right now,” says Jeanne Lawrence, a cell biologist at the University of Massachusetts Medical School in Worcester, and the lead author of the study.

Lawrence and her team devised an approach to mimic the natural process that silences one of the two X chromosomes carried by all female mammals. Both chromosomes contain a gene called XIST(the X-inactivation gene), which, when activated, produces an RNA molecule that coats the surface of a chromosome like a blanket, blocking other genes from being expressed. In female mammals, one copy of the XIST gene is activated — silencing the X chromosome on which it resides.

Lawrence’s team spliced the XIST gene into one of the three copies of chromosome 21 in cells from a person with Down’s syndrome. The team also inserted a genetic ‘switch’ that allowed them to turn on XIST by dosing the cells with the antibiotic doxycycline. Doing so dampened expression of individual genes along chromosome 21 that are thought to contribute to the pervasive developmental problems that comprise Down’s syndrome.

First steps

The experiment used induced pluripotent stem cells, which can develop into many different types of mature cells, so the researchers hope that one day they will be able to study the effects of Down’s syndrome in different organs and tissue types. That work could lead to treatments that address degenerative symptoms of Down’s syndrome, such as the tendency of people with the disorder to develop early dementia.

“The idea of shutting off a whole chromosome is extremely interesting” in Down’s syndrome research, says stem-cell researcher Nissim Benvenisty of Hebrew University in Jerusalem. He anticipates future studies that split altered cells into two batches — one with the extra chromosome 21 turned on, and one with it off — to compare how they function and respond to treatments.

Researchers have previously removed the extra chromosome in cells from people with Down’s syndrome using a different type of genetic modification2. That technique relied on the fact that induced pluripotent stem cells that carry the third copy of chromosome 21 occasionally boot it out naturally — but “it’s a pain in the neck”, says Mitchell Weiss, a stem-cell researcher at the Children’s Hospital of Philadelphia in Pennsylvania. “You can’t control it.”

However, Weiss says that the latest method has its own drawbacks: turning on XIST may not block all gene expression in the extra chromosome, and that could muddle experimental results.

Still, Weiss thinks that the approach could yield fresh treatments for Down’s syndrome — and prove useful for studying other chromosome disorders such as Patau syndrome, a developmental disorder caused by a third copy of chromosome 13.

Source: Nature

 

Genetic advance in Down’s syndrom.

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US scientists say they have moved a step closer to being able to treat disorders caused by an extra chromosome.

They have “switched off” the chromosome that causes the symptoms of Down’s syndrome in human cells in the lab.

The research, published in Nature, could one day lead to new medical treatments for the condition.

Future work may be of real benefit to people with Down’s syndrome, said the UK Down’s Syndrome Association.

Humans are born with 23 pairs of chromosomes, including two sex chromosomes, making a total of 46 in each cell.

People with Down’s syndrome have three – rather than two – copies of chromosome 21.

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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”

Dr Lucy RaymondUniversity of Cambridge

This causes symptoms such as learning disabilities and early-onset Alzheimer’s disease, as well as a greater risk of blood disorders and heart defects.

Gene therapy, which uses genes to treat illnesses, has been attempted for problems caused by a single defective gene. But until now, the idea of being able to silence the effects of a whole chromosome had appeared beyond the realms of possibility, even in the lab.

Now scientists at the University of Massachusetts Medical School have shown that, in theory, this might be possible but would take decades of research.

A team led by Dr Jeanne Lawrence inserted a gene called XIST into the stem cells of a person with Down’s syndrome grown in the lab.

‘Exciting research’

The gene plays a role in normal cell development by switching off one of the two X chromosomes present in female embryos, ensuring daughters avoid a double dose of X chromosome genes.

The experiments showed that the gene was able to silence the extra copy of chromosome 21, helping correct unusual patterns of growth in the cells.

Dr Lawrence told BBC News: “The research means that we have a new way – right away – to study the cellular basis for Down’s syndrome, that could help identify drugs for Down’s syndrome.

“At the same time we have made it conceivable – not necessarily possible or effective, that still needs to be proven – but conceivable that you could use just a single gene to correct the over-expression of the whole chromosome. So it makes genetic therapy for Down’s syndrome more conceivable where it really wasn’t before.”

Commenting on the study, Carol Boys, chief executive of the Down’s Syndrome Association, said it was exciting new research from a very well-respected team.

“The findings could have serious implications for future work that may be of real benefit to people with Down’s syndrome,” she said.

“We are a very long way from understanding how these findings might translate into clinical applications but it could be that they will be of great assistance in the search for conventional treatments for some of the health conditions that affect people with Down’s syndrome.”

Dr Lucy Raymond, from the department of medical genetics at the University of Cambridge, said the group had demonstrated an important proof of concept.

“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.”

Source: BBC