Clinical trial for Rett syndrome launched

December 16, 2010, Children's Hospital Boston

Researchers at Children's Hospital Boston have begun a randomized, placebo-controlled trial to test a potential drug treatment for Rett syndrome, the leading known genetic cause of autism in girls. The drug, mecasermin, a synthetic form of insulin-like growth factor-1 (IGF-1), is already FDA-approved for children with short stature due to IGF-1 deficiency.

The trial, now enrolling patients, marks the beginning of a trend toward drug treatments seeking to modify the underlying causes of , rather than just behavioral symptoms such as or . It follows research in animal models, published in 20091, which suggested that raising IGF-1 levels can reverse features of Rett syndrome by enhancing maturation of synapses —the points of communication between brain cells.

"We expect that therapy that stimulates synaptic maturation will serve as a model for pharmacological treatment of not only Rett syndrome, but of other autism spectrum disorders," says Omar Khwaja, MD, PhD, the study's principal investigator and director of the Rett Syndrome Program in the Department of Neurology at Children's.

Rett syndrome, occurring almost exclusively in girls, is an X-linked neurodevelopmental disorder causing severe cognitive, motor and language problems and autistic behaviors. Other features include loss of purposeful use of the hands; repetitive, stereotyped hand movements; slowed brain and head growth; and heart-rhythm and breathing problems. Although affected children appear normal during their first six months of life, symptoms emerge, tragically, between 6 and 18 months of age, a prime period of synaptic development.

The three-year pilot study will randomize 40 girls (aged 2 to 12) with Rett syndrome to receive the drug, known as Increlexâ (Tercica Inc., a Subsidiary of the IPSEN Group) for five months. The study will use a cross-over design, allowing girls assigned to placebo to switch to active treatment after a six-week "washout" period. The main outcome measures will be improvement in neurodevelopment and in cardiorespiratory function.

Although Rett syndrome used to be seen as a degenerative, irreversible disease, recent research indicates that brain cells aren't actually lost, and the brain is structurally normal – instead, the synapses between cells are weak, preventing brain circuits from maturing. Rett syndrome's usual cause is mutation or deletion of a gene called MeCP2, which itself controls a group of genes that regulate synaptic changes in response to input from the environment. In 2007, working with a mouse model of Rett syndrome, researchers used genetic tricks to restore MeCP2's function in the brain.2 The mice showed a striking recovery, suggesting that Rett syndrome, even when well established, might be a treatable disease – if only synapses could be built back up.

"This was an enormous intellectual proof-of-principle that we aren't wasting time thinking of therapies for girls who are already symptomatic," says Khwaja. "Before, it was thought that if there ever was a treatment, it would have to be given before symptoms appeared, and that once the disease started it couldn't be reversed."

IGF-1, the drug used in the trial, is indirectly regulated by MeCP2. It has been shown to enhance synapse maturation, and in mice missing the MeCP2 gene, treatment with IGF-1 ameliorated several features of their Rett-like disease.1

"There's been a big sea change in how Rett syndrome and other neurodevelopmental disorders are viewed," Khwaja says. "The synapses are very dynamic. They need to be stabilized, and if they don't receive the right stimulus, they'll naturally disappear. That change in paradigm has really affected the way that we look at treatments, and I think it brings a lot more hope."

The new view has already affected the way schooling and education of children with are being approached. "There's more and more evidence in animals that enrichment and schooling can help synapses form and strengthen," says Khwaja. "The battle is getting the girls into appropriate educational settings. If you are repetitive, and give them ways to communicate, they actually can learn, and that's probably because you're reinforcing these synaptic connections."

More information: (1) Tropea D; et al. Partial reversal of Rett Syndrome-like symptoms in MeCP2 mutant mice. Proc Natl Acad Sci U S A. 2009 Feb 10;106(6):2029-34.

(2) Guy J; et al. Reversal of neurological defects in a mouse model of Rett syndrome. Science 2007 Feb 23;315(5815):1143-7.

Related Stories

Recommended for you

Human 'chimeric' cells restore crucial protein in Duchenne muscular dystrophy

March 16, 2018
Cells made by fusing a normal human muscle cell with a muscle cell from a person with Duchenne muscular dystrophy —a rare but fatal form of muscular dystrophy—were able to significantly improve muscle function when implanted ...

Team develops 3-D tissue model of a developing human heart

March 16, 2018
The heart is the first organ to develop in the womb and the first cause of concern for many parents.

Democratizing science: Researchers make neuroscience experiments easier to share, reproduce

March 16, 2018
Over the past few years, scientists have faced a problem: They often cannot reproduce the results of experiments done by themselves or their peers.

Genetic variant discovery to help asthma sufferers

March 16, 2018
Research from the University of Liverpool, published today in Lancet Respiratory Medicine, identifies a genetic variant that could improve the safety and effectiveness of corticosteroids, drugs that are used to treat a range ...

Researchers say use of artificial intelligence in medicine raises ethical questions

March 15, 2018
In a perspective piece, Stanford researchers discuss the ethical implications of using machine-learning tools in making health care decisions for patients.

Study identifies potential drug for treatment of debilitating inherited neurological disease

March 15, 2018
St. Jude Children's Research Hospital scientists have demonstrated in mouse studies that the neurological disease spinal bulbar muscular atrophy (SBMA) can be successfully treated with drugs. The finding paves the way for ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.