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