A class of small molecule known as G9a inhibitors could prove to be the best therapeutic option for people suffering from Prader-Willi syndrome, a rare genetic condition that often leads to obesity. Tested in mice, the compound could improve both life expectancy and growth.
Prader-Willi syndrome affects roughly 1 in 15,000 individuals and is characterised by insatiable hunger and thus often by dangerous weight gain and obesity-related conditions like diabetes. Reduced growth, learning difficulties and behavioural problems are also common.
It is caused by a genetic defect on chromosome number 15. 7 cases out of 10 are the result of missing genetic information on the copy of the chromosome inherited from the father while the mother's copy is silent.
Finding a cure is a priority for researchers. Treatments that have been used to date have not been very effective – growth hormones can help with specific growth problems but dieting strategies have not led to real improvements for patients.
The cells that glowed
In the new study published in the journal Nature Medicine, scientists from Duke University have attempted to find a molecule that would be able to activate the silent maternal copy of the Prader-Willi gene to compensate for the missing paternal genetic information and recover the necessary gene function that would ordinarily be performed by the father's gene.
Working with mouse models of Prader-Willi, the scientists conducted screenings of more than 9,000 compounds. Using fluorescent marker in mouse embryonic fibroblasts, the researchers looked for the small molecules that would trigger the cells to glow. This indicated that they were capable of activating the maternal copy of the Prader-Willi gene.
They found that this was the case for the class of small molecule known as G9a inhibitors. Their action was further confirmed in vitro in human cells from Prader-Willi patients. When given to young mice, the molecules also appeared to increase their lifespan and improve their growth, suggesting potential therapeutic benefits.
"Our findings are promising and indicate that we may have a path forward for the first time to treat the severe, life-limiting features of this genetic disorder," senior author Yong-hui Jiang said.
It has been a month of promising news for patients suffering from Prader-Willi. At the beginning of December, another team of researchers published a study showing that an enzyme known as prohormone covertase (PC1) is deficient in the brain of people with the disorder, paving the way for the development of therapeutic options to raise the level of this enzyme.