In vitro disease modelling and generation and testing of gene therapy approaches for Pitt Hopkins Syndrome

Dr. Kathryn Meyer

Research Institute at Nationwide Children’s Hospital
Columbus, OH

$131,033

2021-2023

Currently the impact of different cell types in PTHS is poorly understood and a more detailed understanding is required for selection of optimal AAV vectors. In addition, the exact disease mechanism is unclear which makes selection of potential therapeutic strategies more difficult. Moreover, the different mutations in PTHS may not have the same effect on these pathways, which could influence the type of therapeutic approach needed for individual patients. Here, we propose to expand our in vitro models to compare the impact of different TCF4 mutations as well as to investigate three gene therapy approaches, all three being highly innovative in their own way. The approaches will 1) validate MeCP2 classical gene replacement; 2) test X-reactivation gene therapy and 3) Utilize a completely novel concept by repurposing U7 small nuclear RNA to modulate TCF4 transcript expression. We will test these approaches in the variable context of patient cell lines as well as share the constructs with established and future PTHS collaborators under collaboration agreements and MTAs. The generated cell lines will also be used for therapeutic evaluation. The findings of these studies will have a major impact on disease understanding and facilitate treatment development using both small molecules or gene therapy approaches.