Investigating the Potential of Antisense Oligonucleotide Therapy for MECP2 Duplication Syndrome

Huda Zoghbi, MD | Baylor College of Medicine

$230,000 AWARDED

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.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.

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