Autism Consortium members publish in PNAS: Mechanism, treatment for Rett syndrome -- top cause autism girls

February 10, 2009

The Autism Consortium, an innovative research, clinical and family collaboration dedicated to radically accelerating research and enhancing clinical care for autism spectrum disorders (ASDs), announced today that several Consortium members published a paper with significance for clinical trials in autism in the Proceedings of the National Academy of Sciences.

The research led by Autism Consortium members Mriganka Sur, PhD, Newton Professor of Neuroscience at the Picower Institute and Head of the MIT Department of Brain and Cognitive Sciences; and Rudolf Jaenisch, PhD, Founding Member, Whitehead Institute and Professor of Biology at MIT, demonstrates for the first time a mechanism for Rett Syndrome and a therapeutic that could be directly applicable to humans. As a result, a clinical trial in humans is in development.

IGF1 Reverses Rett Symptoms in Mice; Clinical Trial Planned

This groundbreaking study demonstrated that by treating mice with a peptide fragment of IGF1, a molecule that is utilized by the brain for neuronal and synaptic development, the symptoms of Rett Syndrome in the mice were largely reversed.

"The next step is to test recombinant human IGF1 which is already available for pediatric use in humans with the hope of treating or reversing Rett Syndrome," said Omar Khwaja, MD, PhD, Director of the Rett Syndrome Program at Children's Hospital Boston and head of the clinical trial team for IGF1. "We are working as quickly possible to develop the protocol, secure funding, and initiate the trial."

"This new study presents promising novel data suggesting that targeting the IGF1 signaling axis may present a useful therapeutic strategy that could ultimately be translated to humans," said Dr. Antony Horton, Chief Scientific Officer at the International Rett Syndrome Foundation. "We are encouraged by this collaboration between scientists and clinicians which is yielding valuable insights into potential new treatments for Rett syndrome."

About Rett Syndrome and the Findings

Rett Syndrome, a neurodevelopmental disorder mainly affecting girls and also the most common basis of autism in girls, is primarily caused by a sporadic mutation in the MECP2 gene on the X chromosome. The MECP2 gene makes a protein, also called MeCP2, believed to play a pivotal role in silencing, i.e. turning off the activity of other genes. The MECP2 mutation causes the regulatory mechanism to fail, which in turn causes other genes to function abnormally.

Rett is a genetic disorder of developmental arrest or failure of brain maturation. This is thought to occur when subsets of neurons and their connections (synapses) are disrupted during a very dynamic phase of brain development. Scientists have been investigating ways to reverse that arrest and therefore, turn brain activity back on.

By crossing into the brain and activating 'IGF1 signaling' - IGF1 binds to its receptor and activates downstream molecules within neurons that make synapses mature. This activity in turn ends the developmental arrest thought to underlie the syndrome.
Using mutant mice in which MeCP2 is deleted, Sur and his co-authors demonstrated a major underlying mechanism for the disorder-synapses in the brain remain immature and showed persistent, abnormal plasticity into adulthood.

"Our research is beginning to show that other forms of autism also have, as their basis, this persistent immaturity of synapses," said Sur. "As a result, an even more exciting and promising aspect of this work is the possibility that IGF1 or similar therapeutics could apply not only to autism caused by Rett Syndrome, but also to other causes of autism as well."

Autism Consortium

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