Investigating the Potential of Antisense Oligonucleotide Therapy for MECP2 Duplication Syndrome

Huda Zoghbi, MD | Baylor College of Medicine

$530,000 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. In collaboration with Ionis Pharmaceuticals Inc., we developed an antisense drug (ASO) that can specifically reduce the levels of MeCP2.We have used the ASO molecule to reverse the symptoms of MECP2 duplication syndrome in mature adult symptomatic mice and showed that normalizing MeCP2 levels resulted in improvement of all the features of the syndrome. Even when starting the treatment at the advanced age of 6-8 months the animals benefited and stopped having seizures. These results give us hope that there is a potential to reverse the symptoms in people if we can deliver the ASO and safely control the MeCP2 levels. To prepare for clinical studies we must generate and characterize mice, that, like people with duplication, have two copies of the human gene (and no mouse gene). We have generated such mice and are now characterizing them. We also need to use a new method of ASOs administration that has been shown successful in human infants. In contrast to our previous work, where the ASOs where gradually infused over a period of 4 weeks using mini-osmotic pumps, in this new research we will use the single -bolus intracerebroventricular injection strategy. Based on the experience of our lonis collaborators in recent clinical trials, the single-bolus injection strategy results in a much broader distribution of the drug, compared to slow and gradual infusion. Because having the right MeCP2 levels is critical for brain function, we must determine the ideal dose of ASO that bring MeCP2 levels from twice normal to normal. We need to define the dose carefully so that the levels do not dip below the expected normal to avoid complications from too little MeCP2. All these studies to optimize the infusion of the ASO, the dosing, and the titration of the dose will be done in the new mouse model, that, like the humans, expresses two copies of the human gene.

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