MECP2 Duplication Syndrome Research


Five Priority Interventions for MECP2 Duplication Syndrome

by the Rett Syndrome Research Trust

Identifying Drugs and Drug Targets to Normalize MECP2 Levels and Treat MDS

Dr. Huda Zoghbi, Baylor College of Medicine


MECP2-duplication syndrome (MDS) occurs when there are one or more extra copies of the MECP2 gene. The excessive MeCP2 protein made by the extra copy of the gene severely affects brain function.  From our previous RSRT-funded research, we discovered that MDS symptoms can be eliminated in mice if MeCP2 levels are corrected. A drug to lower MeCP2 would be the simplest way to do this for patients, so for this project our goal is to find drugs that can reduce MeCP2 protein levels or identify good drug targets that can be used to design drugs to treat MDS.

We are taking two major approaches to find drugs that lower MeCP2. (1) We’re testing almost all of the current FDA-approved drugs to see if any of them can affect MeCP2 levels. Such strategies have worked to find treatments for other diseases, and should we find one, the path to clinical use will be dramatically accelerated since the drug will already be available and its safety profile will be known. (2) We are testing every gene in the genome to identify those that regulate MeCP2 levels. Once we identify regulators of MeCP2 we can pursue strategies to identify drugs that might inhibit them to then reduce MeCP2. We’re targeting regulators of MeCP2 rather than MeCP2 itself because MeCP2 can’t perform chemical reactions so is difficult to inhibit with drugs, whereas many regulators can more easily be targeted. We previously performed pilot studies of fewer genes to test the feasibility of this approach and found several MeCP2 regulators. We then used a drug to inhibit one of them in MDS mice and saw that it improved some of the mice’s symptoms. For this project, we are following up on these regulators, and any more we discover, with additional mouse studies to determine which are the best drug targets and if they can work even better when used in combination.

We are trying to find as many drug targets and drugs as possible to maximize our chances of finding those that are most effective and safe, and can be brought to the clinic to treat MECP2-duplication syndrome

Key steps needed to translate our pre-clinical findings

Dr. Huda Zoghbi, Baylor College of Medicine


In preparation for clinical studies aimed to test MECP2-ASOs as a potential therapy for MDS, we first need to complete the following steps:

1.Characterize our new humanized mouse model of MDS (two copies of the human gene and no mouse gene) in great details to prove its validity as a good model.
2.Use a new method of ASOs administration that has been shown successful in human infants. In contrast to our previous work, where the ASOs were gradually infused over a period of 4 weeks using mini-osmotic pumps, in this proposal we will use the single-bolus intracerebroventricular injection strategy. Based on lonis’ experience with big animals and recent clinical trials, the single-bolus injection strategy results in a much broader distribution of the drug, compared to slow and gradual infusion. Of course, we must show that this acute bolus is safe for MECP2.
3.Screen for new high-grade ASOs that do not induce inflammation or any secondary toxicity.
4.Establish the lowest tolerated levels of acute MeCP2 reduction in adult mice. For this study, we will first use mice carrying a single human MECP2 allele, as these animals are healthy and more appropriate to determine the ASO dosage that brings MeCP2 to the lowest tolerated levels. The results of this study will help us better design the ASO doses necessary to normalize MeCP2 in our humanized MDS model.
5.Perform pharmacokinetic (ideal dose and how long it lasts for) and tolerability studies in mice with two human MECP2 alleles.

These studies are required by Ionis and any industry standard for us to proceed to clinical studies. We fully agree that all of the above steps are necessary to ensure safety and increase the odds for successful clinical studies.


Investigating the Potential of Antisense Oligonucleotide Therapy for MECP2 Duplication Syndrome

Dr. Huda Zoghbi, Baylor College of Medicine

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.

Recent data show that MECP2, at the normal level, is required for proper postnatal neurological functions. Reversibility of symptoms has been demonstrated in a mouse model of Rett syndrome upon normalization of MECP2 levels, highlighting the surprising potential plasticity of the adult brain upon correction of the molecular mechanisms underlying these disorders. 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.

Pharmaceutic Screen

Dr. Huda Zoghbi, Baylor College of Medicine

The experiment involves the screening of FDA approved pharmaceutics that could potentially regulate the levels of the MECP2.


Genetic Reversal


The study has been undertaken in the lab of an eminent physician-scientist, Dr. Huda Zoghbi, at Baylor College of Medicine in Houston, TX.  Through sophisticated genetic engineering, the Zoghbi lab will design an experiment that will carefully analyze disease symptoms in an animal model following deactivation of the second MECP2 gene. Encouraging data suggesting the disease is reversible will set the stage for a drug development initiative.

Please visit the RSRT website to read about a previous experiment on Rett Syndrome that is similar to this undertaking:


Gene Therapy: Vector-Based RNAi

Dr. Kevin Foust

The Gene Therapy experiment in the lab of Dr. Kevin Foust involves using Vector-Based RNAi. Essentially, what this project endeavors to do is knockdown or knockout the duplicated MECP2 gene through RNAi.

For more understanding of Vector Based RNAi Technology:

Results of a Phase 1 clinical trial from Alnylam Pharmaceuticals involving the same technology:

Downloadable Scientific Papers

Dr. Huda Zoghbi Reversal

Van Esch