Development and characterization of a pig model of AS | $201,720.00

Loss of the maternally inherited ubiquitin E3A ligase (UBE3A) gene causes Angelman syndrome (AS), a devastating neurological disorder characterized by intellectual disability, ataxia, absent speech, seizures, and a happy disposition [1]. The UBE3A gene is imprinted with maternal-specific expression in the brain and biallelic expression in all other cell types. Consequently, mutations affecting the maternal UBE3A allele cause AS, whereas mutations affecting the paternal allele are non-penetrant. Currently, there are no effective therapies to treat AS patients. There are, however, a number of promising therapeutic strategies recently identified using mouse models of AS. Huang et al. (2011) demonstrated that topoisomerase inhibitors — chemotherapeutic agents used to treat cancer — reactivate the paternal Ube3a allele in the adult mouse brain [2]. Topoisomerase inhibitors are highly toxic, so their use as an AS therapy at this point is unclear. Nevertheless, this study demonstrated that the Ube3a imprint is amendable to pharmacological intervention and may serve as a viable AS therapeutic. Daily et al. (2012) showed that gene therapy improves cognition in adult AS mice, indicating that AS is indeed treatable [3]. There are currently numerous laboratories working to identify therapies for AS, including treatments that have shown promise in mouse models of other conditions (e.g., Rett and Fragile-X syndromes); however, there is a critical need for preclinical models more physiologically similar to humans to validate and evaluate these promising therapeutics. Here, we propose to develop and characterize a pig model of AS. Our long-term goals are to understand the pathogenesis of AS and develop therapies to treat this debilitating condition. Our central hypothesis is that the AS pig model will recapitulate many of the phenotypes characterized by AS, and serve as a final-stage preclinical model for testing promising therapeutics. The objectives of this proposal are to generate a pig model with a loss-of-function mutation in the porcine UBE3A gene and characterize it for AS relevant phenotypes.