Experimental therapy for Prader-Willi syndrome shows promise in mice

Genetic information passes to a child in a pair of chromosomes -- one from the father and one from the mother. PWS is caused by genetic changes along a section of chromosome 15 called the Prader-Willi critical region. Under normal circumstances, genes in this region are inactive, or silenced, on maternal chromosome 15 but active on paternal chromosome 15. In PWS, however, the critical region on the paternal chromosome either is inactive or missing. Infants with PWS fail to thrive and have altered metabolisms and trouble feeding. However, as they get older, they become compulsive overeaters.

In the study, researchers found two drugs, called UNC0638 and UNC0642, capable of activating maternal PWS genes in cells from a patient. They targeted maternal genes because, unlike paternal genes, they are consistently available in PWS patients. The study team then tested UNC0642, which had more favorable pharmacological features, in a mouse model of PWS. These mice grow poorly, like infants with PWS, and do not survive. The experimental drug activated maternal PWS genes, and the treated mice had better growth and weight gain than untreated mice, with 15 percent surviving to adulthood without serious side effects.

UNC0638 and UNC0642 work by inhibiting the activity of a protein called G9a, which together with other proteins packs the maternal genes tightly in the chromosome. Overall, the study shows that this type of therapy may be beneficial for treating PWS, but researchers will need to evaluate the drugs' effects on other disease symptoms, such as compulsive overeating and obesity.

Additional support for this study was provided by NIH's National Institute of General Medical Sciences and the Foundation for Prader-Willi Syndrome Research.