For the first time, scientists have switched off a Down's syndrome chromosome, raising hope for possible treatment of the genetic disorder characterised by cognitive impairment.
Scientists say the in vitro discovery opens new avenues for future chromosome therapy.
Researchers at The University of Massachusetts Medical School (UMMS) in US established that a naturally occurring X chromosome "off switch" can be rerouted to neutralise the extra chromosome responsible for trisomy 21, also known as Down syndrome.
The discovery provides the first evidence that the underlying genetic defect responsible for Down syndrome can be suppressed in cells in culture (in vitro).
This paves the way for researchers to study the cell pathologies and identify genome-wide pathways implicated in the disorder, a goal that has so far proven elusive.
Doing so will improve scientists' understanding of the basic biology underlying Down syndrome and may one day help establish potential therapeutic targets for future therapies.
"Our hope is that for individuals living with Down syndrome, this proof-of-principal opens up multiple exciting new avenues for studying the disorder now, and brings into the realm of consideration research on the concept of 'chromosome therapy' in the future," said lead author Jeanne B Lawrence.
Humans are born with 23 pairs of chromosomes, including two sex chromosomes, for a total of 46 in each cell. People with Down syndrome are born with three (rather than two) copies of chromosome 21, and this "trisomy 21" causes cognitive disability, early-onset Alzheimer's disease and a greater risk of childhood leukemia, heart defects and immune and endocrine system dysfunction, said researchers.
Unlike for genetic disorders caused by a single gene, genetic correction of a whole chromosome in trisomic cells has been beyond the realm of possibility, even in cultured cells.
Harnessing the power of the RNA gene called XIST, which is normally responsible for turning off one of the two X chromosomes found in female mammals, scientists have shown that the extra copy of chromosomes 21 responsible for Down syndrome can be silenced in the laboratory using patient-derived stem cells, researchers said.
The natural function of the XIST gene, located on the X chromosome, is to effectively silence one of the two X chromosomes in female cells, making expression of X-linked genes similar to that of men, who have just one X chromosome.
The large XIST RNA is produced early in development from one of the female's two X chromosomes, and this unique RNA then "paints" the X chromosome and modifies its structure so that its DNA can't be expressed to produce proteins and other components.
This effectively renders most of the genes on the extra chromosome inactive, researchers said.
The study was published in the journal Nature.