Unlike Rett Syndrome, which is caused by mutations or deletions in the MECP2 gene, the symptoms that arise from the duplication syndrome are caused, as the name suggests, by having an area of the X chromosome (Xq28), which includes the MECP2 gene, erroneously duplicated. The section duplicated may vary from individual to individual and may also contribute to the severity of the disease.
The syndrome has been diagnosed mostly in boys. The majority inherit the duplication from their mothers who are typically asymptomatic due to favorable X chromosome inactivation (the moms have inactivated the X chromosome that harbors the duplication). Carrier mothers have a 50% chance of passing on the duplication to their children.
The MECP2 Duplication Syndrome may be quite prevalent. Preliminary studies suggest that 1% of cases of X-linked mental retardation may be due to this syndrome. The core phenotypes in boys include infantile hypotonia, mild dysmorphic features, developmental delay, absent to minimal speech, recurrent infections, progressive spasticity especially of the lower limbs, ataxia, autistic features, and seizures. Females with MECP2 duplication without X chromosome inactivation skewing have been reported and present similarly to boys.
MECP2 Duplication Syndrome Fund at RSRT
In an effort to immediately leverage RSRT’s deep knowledge base and well established global scientific networks the MECP2 Duplication Syndrome Fund at RSRT was created in late 2010. The Fund puts the intellectual and scientific resources of RSRT immediately to work for the MECP2 Duplication/Triplication Syndrome community.
The Fund exclusively supports projects devoted to the study and means of treatment of MECP2 Duplication Syndrome. 100% of every dollar contributed is invested in research – not a single penny goes to overhead.
Funds raised to date: $1,222,000
The MECP2 Duplication Syndrome Fund is actively raising funds for the ASO project (see below) in the lab of Huda Zoghbi. The budget is $230,000 and $213,000 has been raised leaving a balance of $17,000. As soon as these funds are raised additional projects can be supported.
Ongoing Fund projects
Investigating the Potential of Antisense Oligonucleotide (AS) Therapy for MECP2 Duplication Syndrome
Huda Zoghbi (Baylor College of Medicine)
$230,000 / 2 year project
MECP2 duplication syndrome is a neurological disorder caused by the duplication of genetic material on chromosome X, spanning the MECP2 gene. As a result of the duplication, the MeCP2 protein is excessively produced at two times the normal levels. This proposal will explore the use of a drug-like molecule to reverse the symptoms of MECP2 duplication syndrome, first in an animal model and later in cells derived from patients.
In collaboration with ISIS Pharmaceuticals Inc., we developed an antisense drug that can specifically reduce the levels of MeCP2. We will first screen for the most effective MECP2-specific drugs in vivo using our MeCP2-Tg1 mice and then test the ability of the selected drugs to reverse symptoms in the mice at the behavioral, molecular and electrophysiological level. We will next test the effectiveness of the drugs in reversing the cellular and molecular phenotype of neural cells derived from MECP2 duplication patients. In order to generate MECP2 duplication syndrome neural cells, skin biopsies have been taken from patients and skin cells (fibroblasts) have been derived and cultured in our laboratory. In collaboration with the Human Stem Cell Core at Baylor, we will reprogram the human fibroblasts to generate stem cells that could be then re-differentiated into neurons.
If we establish that normalization of MeCP2 levels by treatment with the selected drugs rescues the duplication traits, this would be very exciting for the MECP2 duplication families. In addition, the establishment of a new patient-specific cellular model of the disease will open a new area of research and a new pre-clinical tool to screen for modulators of MeCP2 levels.
Is MECP2 Duplication/Triplication Syndrome Reversible?
Huda Zoghbi (Baylor College of Medicine)
$236,000 / 3 year project (fully funded)
The dramatic reversal of Rett symptoms in mice described by Adrian Bird in 2007 opened the field to questions that must now also be explored in the MECP2 Duplication Syndrome. We know that in Rett, restoration of proper MeCP2 function in mice only days away from death brought them back to health. Would elimination of the influence of excess MeCP2 in the Duplication Syndrome have a similarly dramatic effect? The first project funded by the Fund will answer this question. The lab of Huda Zoghbi at Baylor College of Medicine is conducting experiments to answer whether restoring proper amounts of Mecp2 in an animal model of the syndrome will reverse symptoms. If symptoms can be reversed is there a time period or can reversal also occur in adults, as in Rett?
A Forward Genetic Screen to Identify Druggable Modulators of MECP2 Levels
Huda Zoghbi (Baylor College of Medicine)
$733,289 / 4 year project (fully funded)
Dr. Zoghbi will screen compounds in search of any that can reduce levels of MeCP2 for the duplication/triplication syndrome. Any positive “hits” could form the foundation for drug discovery efforts.
Gene Therapy Approach to Treating MECP2 Duplication Syndrome
Kevin Foust, Ph.D.
Ohio State University
$39,340 / 1 year project (fully funded)
The duplication syndrome is caused by having an extra copy (or two) of the MECP2 gene and sometimes other genes in the vicinity. In theory, reducing the amount of MeCP2 protein should improve the disease. Dr. Foust will use adeno-associated virus (AAV) to deliver RNA interference to lower the amount of MeCP2 protein. If successful the project will provide proof-of-concept data showing that MeCP2 reduction is a therapeutic option for patients.
We hope that the families affected by MECP2 Duplication Syndrome and those who know and care about them will be encouraged and energized by the ongoing research. Your participation and commitment are more than welcome: they are a necessity. It is your energy that will determine the speed and intensity of MECP2 Duplication Syndrome research.
The next $230,000 raised by the Fund will be used for the ASO project in Dr. Zoghbi’s lab. Additional funds can be invested in new projects.
You can support the MECP2 Duplication Syndrome Fund through the following ways:
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Rett Syndrome Research Trust
67 Under Cliff Road
Trumbull, CT 06611
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Reverse MECP2 NYC Gala
November 2, 2015
New York, NY