RSRT's plan was developed in concert with, and will be executed by distinguished scientists who are thought-leaders in their field.

RSRT is currently supporting key projects which not only offer the possibility of curing Rett Syndrome and related disorders, but may also identify drugs that could rapidly enter clinical trials to improve the lives of suffering individuals in the near term.  It is our intention to expand beyond these initial projects as soon as resources allow.

Identification of drugs or genes that activate the silent MECP2 gene
Antonio Bedalov, M.D., Ph.D.
Fred Hutchinson Cancer Research Center

This project will attempt to identify either drugs/compounds or genes that will activate the silent MECP2 on the inactive X chromosome. This will be achieved by developing a sensitive assay which can detect activation of the silent MECP2. The assay will then be screened using both a chemical and genetic approach. Ideally this project will identify a combination of drugs and genes that together can be used to reactivate the silent MECP2 on the inactive X chromosome. This project will be undertaken in the laboratories of Antonio Bedalov, M.D., Ph.D. at Fred Hutchinson Cancer Research Center in Seattle, WA.

Identification of the mechanisms that silence the MECP2 gene on the inactive X chromosome
Marisa Bartolomei, Ph.D.
University of Pennsylvania

A synergistic project to the one just described this effort is also focused on activating the silent MECP2 gene on the inactive X. Dr. Bartolomei will attempt to identify the epigenetic modifications that keep MECP2 silent. Our hope is that, once identified, these modifications can be reversed with drug(s). 

Novel insights in MeCP2 function suggests new therapeutic strategies
Stavros Lomvardas, Ph.D.
University of California San Francisco

This experiment leverages the discovery that MeCP2 deficient olfactory receptor neurons (ORN) have a very robust readout; they co-express molecules that are never expressed in the same neuron in wild type mice. Dr. Lomvardas will capitalize on this finding to screen for drugs that can reverse the deficit – in other words find drugs, using high throughput screens (HTS) that can turn off one of ectopically expressed molecular markers.

In vivo screen of drugs and drug-like compounds
Andrew Pieper, M.D., Ph.D.
University of Texas Southwestern Medical Center in Dallas

This project will test FDA approved drugs and compounds in mice models of Rett to identify Hits that improve disease-related signs in the animals.  Any drugs or compounds found to alleviate the symptoms or progression of the disease in mice will form the basis of advanced drug discovery programs; approved drugs can be fast-tracked to clinical trials.  This project will be undertaken in the laboratory of Andrew Pieper, Ph.D. at University of Texas Southwestern Medical Center in Dallas with the support of Steven McKnight, Ph.D.
 

In vivo evaluation of specific drugs in mouse models of MECP2 disorders
Huda Zoghbi, M.D.
Baylor College of Medicine

This project is a thorough evaluation of specific drugs in the various mouse models of MECP2 disorders: the knockout, the truncated Mecp2 and the Mecp2 over-expressing mouse lines. Instead of completely lacking the Mecp2 gene as in the knockout mouse, the truncated Mecp2 mouse expresses the first portion of the MECP2 protein. These animals have milder deficits with a much slower disease progression, and are therefore a model of milder forms of Rett Syndrome. Interestingly, too much MECP2 also causes a severe neurological disease, called MECP2 duplication syndrome. The MECP2 over-expressing mouse carries two copies of the MECP2 gene and is a relevant model of MECP2 duplication syndrome in humans.  These experiments will be performed in the laboratory of  Huda Zoghbi, M.D. at Baylor College of Medicine in Houston.
 

Identification of specific brain regions responsible for Rett symptoms
Adrian Bird, Ph.D.
University of Edinburgh
Co-Investigators: Nathaniel Heintz, Ph.D (Rockefeller University); Gernot Riedel, Ph.D. (Aberdeen University); Stuart Cobb, Ph.D. (University of Glasgow)

Jointly funded by RSRT, Autism Speaks and the Medical Research Council of the UK, this project is an international collaboration to identify specific brain regions responsible for disease symptomology. The work is performed in the UK laboratory of Adrian Bird, Ph.D, with key technological contributions from Nathaniel Heintz, Ph.D. of Rockefeller University. The Heintz lab is a pioneer in the BAC (bacterial artificial chromosome) techniques which allow efficient and reproducible cell-specific expression of proteins of interest in vivo. For this project BACs are used to turn on the normal MECP2 gene in specific brain regions of the knockout model. Similar technology will also be employed in wildtype models to turn off the normal MECP2 gene in specific brain regions. The identification of the brain regions involved with symptoms of the disease may suggest novel treatment approaches directed towards specific neurotransmitter systems or signal transduction pathways. Moreover, this knowledge will lay the foundation for potential gene therapy or protein replacement approaches directed to specific brain regions of individuals with Rett Syndrome and MECP2 spectrum disorders.  
 

Identification of gene modifiers that ameliorate Rett symptoms
Monica Justice, Ph.D.
Baylor College of Medicine

An emerging field of interest is that of genetic modifiers that impact the severity of disease. Rett Syndrome is ideal for modifier screening for two reasons: a) it has been shown to be reversible in mice and b) the existence of girls who do not have Rett symptoms despite having common mutations in MECP2.  It is likely that these girls have mutations in other genes that confer protection from damaged MECP2.  This project aims to identify these advantageous gene modifiers and provide novel avenues for therapeutic intervention. The project is underway in the laboratory of Monica Justice, Ph.D. at Baylor College of Medicine. 
 

Banner image - Neurons in the dentate gyrus (part of the hippocampus) of a genetically modified "brainbow mouse". The image is taken using a confocal microscope. 
Photograph courtesy of Jean Livet/Nature