| dc.description.abstract | Methyl-CpG-Binding Protein 2 (MECP2)-related neurodevelopmental disorders, including Rett syndrome (RTT), MECP2 Duplication syndrome (MDS) and Pitt-Hopkins syndrome (PTHS) are rare, pediatric diseases with devastating outcomes. The complex pathophysiology of these disorders has raised challenges in developing effective treatments. However, MECP2-related disorders exhibit comparable phenotypes both in the clinic and in preclinical animal models, which proposes the possibility that these disorders could be responsive to similar therapeutic strategies. Clinical and transcriptomic data could provide insights into these mutual and potential therapeutic targets. The following dissertation project explores two arms of the therapeutic drug discovery efforts, genetic and pharmacological interventions, and employs preclinical animal models of disease and several molecular biology and in vivo neuropharmacology techniques to evaluate the safety and efficacy of these treatment strategies. The results illustrate that MeCP2 genetic supplementation in a RTT mouse model harboring a clinically prevalent MeCP2 mutation, Mecp2 R133C, poses safety concerns, especially in regard to the symptomatic domains of motor, anxiety and cognition. Interestingly, a similar approach of genetically increasing MeCP2 expression could be advantageous in mice modeling PTHS, as observed with global transcriptomic changes and with the correction of behavioral phenotypes comparable to that in RTT animals. Moreover, pharmacologically targeting the group II metabotropic glutamate receptors (mGlu2 and mGlu3), two proteins with significant decreases in expression in post-mortem brain tissues from RTT patients, alleviates cognitive abnormalities, specifically in associative learning and memory, in RTT and MDS model mice. Overall, this dissertation aims to provide information pertinent to the clinical trajectory of gene therapy and potential novel therapeutics targets for MECP2-related neurodevelopmental disorders. | |
