Rett syndrome is an inherited disease affecting one of 10,000 girls born and is the most common basis of autism in girls. Infants with the disease appear to develop normally for their first six to 18 months, at which point their movement and language skills begin to deteriorate. Loss of speech, reduced head size, breathing and heart rhythm irregularities, and autistic-like symptoms are common by age four. Some symptoms may be mediated with prescription drugs, but no cure or truly effective treatment for the disease exists.

In a study appearing February in the Proceedings of the National Academies of Sciences, researchers showed that daily injections of an active fragment of IGF-1 in mice that expressed Rett-syndrome like symptoms could significantly reduce movement and respiratory irregularities. Although treated mice were not cured, the outcome is reason for optimism.

"This is the first realistic way for a drug-like molecule injected into the bloodstream to relieve Rett syndrome symptoms," says Whitehead Member Rudolf Jaenisch, whose lab collaborated with the lab of MIT and Picower scientist Mriganka Sur in the research.

In approximately 85% of girls with Rett syndrome, the disease is caused by loss of function of the MeCP2 gene, which is highly expressed during nerve cell maturation. Lack of MeCP2 expression impedes nerve cell growth, keeping the cells from forming projections, called spines, which are used for nerve-cell-to-nerve-cell communication. Recent genetic studies have shown that in mice with blocked MeCP2 expression, turning MeCP2 back "on" nudges the mice towards normal movement and lifespan—an indication that the disease could be reversible.

Although researchers have known which gene causes the vast majority of Rett syndrome cases, they have until now been unable to promote nerve cell maturation through administration of a drug, protein, or small molecule.

While researchers in Sur's lab had discovered that increased brain levels of IGF-1 promoted maturation of synapses, the connections between nerve cells that are the basis for brain functions, Emanuela Giacometti, a graduate student in Jaenisch's laboratory, was theorizing that IGF-1 might also increase the nerve cell spines in the lab's mouse model of Rett syndrome. Such mice lack the MeCP2 gene and at four to six weeks display symptoms quite similar to those in girls with Rett Syndrome, including difficulty walking, lethargy, and breathing and heart rhythm irregularities.

In a collaboration with the Sur lab to test how IGF-1 might affect these mice, Giacometti administered to two-week-old Rett mice daily injections of IGF-1 fragment. At six weeks, treated mice were significantly more active, had more regular breathing, and had more normal, regular heart rhythms than did untreated mice. In addition, the brains of treated mice were heavier and showed more nerve cell spines.

"Although the treated mice get better and their symptoms don't progress as fast as they normally would, the treated mice still get the symptoms. So it's definitely not a cure, but it could be a co-therapy," Giacometti says.

Sur is also excited by the prospect of finding a drug treatment for Rett syndrome and other forms of autism. IGF1 is approved by the US Food and Drug Administration (FDA) to treat severe IGF-1 deficiency. "This represents a way forward towards clinical trials and a mechanism-based treatment for Rett Syndrome. We very much hope our research can offer some help for the patients who have this terrible disorder."

This work is supported by the Rett Syndrome Research Foundation, the National Institutes of Health, the Simons Foundation, the Marcus Family Foundation and the Autism Consortium.

Rudolf Jaenisch's primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also a professor of biology at Massachusetts Institute of Technology.

Mriganka Sur is the Paul E. Newton Professor of Neuroscience at MIT's Picower Institute for Learning and Memory and head of the MIT Department of Brain and Cognitive Sciences.

Note: If no author is given, the source is cited instead.

• Children's Health
• Birth Defects
• Chronic Illness

• Autism
• Huntington's Disease
• Depression

• Rett syndrome
• Autistic spectrum
• Sex linkage
• Diabetes mellitus type 2
• Embryonic stem cell
• Huntington's disease