$9,000,000 AWARDED

MECP2 Consortium

The discovery that mutations in the MECP2 gene are associated with Rett Syndrome stimulated scientific research to define the role of the protein product, MeCP2, in normal development. This research has defined numerous important functions of the MeCP2 protein and identified potential therapeutic targets for treating the symptoms of Rett Syndrome. Despite significant progress, it is not yet possible to explain in molecular terms exactly how the mutation in MECP2 causes Rett’s particular constellation of symptoms. As we are trying to cure disorders caused by faulty MeCP2, RSRT is continuing to fund research to fully understand the critical functions of MeCP2 .

To accelerate progress, we rejected the conventional practice of laboratories working in isolation and instead convened three powerhouse scientists to work collaboratively: The MECP2 Consortium.

We will continue to provide the necessary financial resources and infrastructure, and coordinate the collaboration, including in-person meetings. Being able to thrash out ideas and explore different ways of looking at Rett with top class scientists from different backgrounds has elevated everyone’s research. The partners have fully committed to the Consortium idea and as a result no one feels inhibited about robustly questioning the others. This kind of free and frank exchange keeps us on our toes and always makes research better.

Being able to thrash out ideas and explore different ways of looking at Rett with top class scientists from different backgrounds has sharpened up everybody’s research. All the partners have fully committed to the Consortium idea and as a result no one feels inhibited about robustly questioning the others. This kind of free and frank exchange keeps us on our toes and always makes research better.

ADRIAN BIRD

University of Edinburgh

Advancements to Date

Gene Therapy Proven to Work

The Consortium has reported significant progress. The Mandel and Bird labs showed, for the first time, a dramatic reversal of symptoms in fully symptomatic Rett mice using gene therapy techniques that could be utilized in people. This seminal research provided the basis for RSRT to recruit expert scientists into our Gene Therapy Consortium.

NOVEL BINDING PARTNER IN MECP2

The Bird lab discovered that the function of the Rett protein, MeCP2, depends on its ability to recruit a novel binding partner, NCoR/SMRT to DNA. Disrupt that ability and the symptoms of Rett ensue. This discovery could lead to an improved gene therapy approach and is currently being assessed in our Gene Therapy Consortium.

LONG GENE MISREGULATION DISCOVERED

The Greenberg lab built on the work of the Bird lab and discovered that MeCP2 has a unique role in the regulation of very long genes. These very long genes are predominantly expressed in the brain and appear to be critical for normal brain function. The lab has identified several drugs that normalize long gene expression in cellular models and are currently assessing efficacy in mouse models of Rett. This research has identified promising new classes of therapeutics with potential for treating Rett Syndrome.

POTENTIAL TO CORRECT MUTATIONS

The Mandel lab  has demonstrated that it is possible to directly edit specific mutations in neurons. Approximately a third of the mutations that cause Rett  are point mutations, mutations where only one of the 70,501 nucleic acids in the MECP2 gene is incorrect. The Mandel lab has demonstrated that it is possible to correct specific mutations at the RNA stage, before the protein is synthesized. Current efforts are focused on increasing efficiency and specificity of the editing.

The Growing Toolbox of Rett Mouse Models

The Bird lab has created mouse models of three common human mutations (T158M, R133C, R306C) and found correlations between mutation and severity and protein stability. In addition to increasing our understanding of how the mutations cause Rett Syndrome, these humanized mouse models are also proving useful for assessing therapeutics, such as our gene therapy program, that focus on restoring normal human MeCP2. Furthermore, this investment will be leveraged by research in other labs as the mouse models are available to scientists worldwide.

THE PATHOPHYSIOLOGY OF RETT

The Greenberg lab recently discovered sites on MeCP2 that are modified in response to neuronal activity. Because neuronal activity is critical for normal neurodevelopment and function, the lab is investigating how these activity-dependent modifications of MeCP2 are relevant to the pathophysiology of Rett.

The MECP2 Consortium is a model for something much bigger: how neuroscience overall needs to operate so that we can find therapies and cures for disease. The rigor and pace of scientific progress is much greater with the three labs working together than would be possible if each lab were working alone. Monica has been essential to keeping the Consortium on target and helping make sure the scientists in the Consortium continue to work together effectively over time.

MICHAEL GREENBERG

Harvard University

In Their Own Words

The Consortium works in large part due to the commitment of the three principal investigators. However that commitment is also required of all the lab members – the people who actually are in the lab day in day out executing experiments.

Harrison Gabel (Greenberg lab)
It is truly unprecedented to have three powerhouse labs that work on the mechanism of MeCP2 get together for meetings and share their most recent data. The reality is that under any other circumstances we would be competing and largely keeping secrets from one another until the data were published. This Consortium breaks down these walls and as a result the science moves much faster. Our group meetings are essential to critically assessing our work. Each lab group has its own “world view,” and having that view shaken up every six months is very constructive.

Matt Lyst (Bird lab)
Sharing current data between labs means we all receive input from people in the field but outside of our own labs at a much earlier stage than would normally happen.

John Sinnamon (Mandel lab)
Attending the RSRT Consortium meetings is a wonderful experience. There is a collaborative atmosphere you don‘t see at large scientific meetings and everyone is focused on understanding the biology of MeCP2 so that we can understand Rett Syndrome. For me personally, it‘s very powerful to meet parents of girls with Rett and to talk to them about my research. It provides a reminder of what I am working towards and gives the families an opportunity to talk one on one with the scientists.

Current Projects

Learn About our Roadmap to a Cure