A class of cholesterol-lowering drugs called statins decreased Rett syndrome symptoms in a rodent model, suggesting that targeting cholesterol pathways may be key for treating this disorder.

Rett syndrome is a genetic disorder that is X-linked, so it primarily affects girls. The neurological disorder begins to affect development in toddlers, who gradually lose their speech and motor abilities. Some patients also have seizures and severe digestive problems, and most are unable to take care of themselves as adults.

Monica Justice (Baylor College of Medicine, Houston, TX) led a study to search for possible gene targets for the treatment of this disorder. She and her colleagues injected healthy male mice with a chemical called ENU that mutates sperm cells randomly. Then they mated the males to females of the Rett mouse model, which have a mutated Mecp2 (methyl-CpG-binding protein 2) gene. Mecp2 turns other genes on or off by disrupting chromatin.

Next, they screened the offspring of these mice to see which ones had fewer symptoms of Rett syndrome, despite having mothers with the Mecp2 mutation. A group of the offspring performed better on mobility tests and lived longer than most mice with the Mecp2 mutation, indicating that the randomly induced mutations in their genes had 'rescued' them from developing symptoms of Rett syndrome. Justice and her team screened these mice for the gene mutations that modified the effects of Mecp2. A gene called squalene epoxidase (Sqle), which encodes a rate-limiting enzyme in the cholesterol biosynthetic pathway, was the most drug-targetable gene found in the screen (Nat. Genet. published online 28 July 2013; doi:10.1038/ng.2714). The researchers wondered whether inhibition of this pathway was the mechanism that rescued the animals.

Mice with Mecp2 mutations were treated with several different statins. Although statins do not affect Sqle specifically, they interfere with another rate-limiting enzyme in cholesterol metabolism. All of the statins tested improved symptoms in these mice. Similar to the rescued mice in the gene mutation experiment, the statin-treated mice showed improvements in mobility, gross motor function, overall health and lifespan compared to untreated mice with the Mecp2 mutation.

Cholesterol metabolism is also being studied in connection with other neurological diseases, including fragile X syndrome, neurofibromatosis and amyotrophic lateral sclerosis. The next step for the researchers will be to test whether other drugs that affect cholesterol metabolism provide similar results. Furthermore, such drugs must be tested in clinical trials with children before they can be approved for treatment of Rett syndrome.