Like humans with Angelman syndrome (AS), mouse models of AS exhibit seizures, impaired cognition, abnormal sleep, and motor-defects; however, the expressivity and penetrance of these phenotypes are strain- and age-dependent and largely less pronounced relative to those observed in individuals with Angelman syndrome.
In 2015, FAST and FAST Australia funded Dr. Scott Dindot at Texas A&M University to develop a pig model of Angelman syndrome. There was a critical need for preclinical models that were more physiologically similar to humans to evaluate and validate promising therapeutics in a more translatable manner than that of rodents. Therefore, to develop an improved animal model that could potentially predict more translatable clinical outcomes in preclinical studies, as well as a model that could be more readily utilized in the development of new pharmacodynamic biomarkers, an AS pig model was generated using CRISPR/cas9 and somatic cell nuclear transfer.
Recently, FAST awarded a grant in the amount of $1.1 Million to Dr. Scott Dindot at Texas A&M University to use the AS pig model to develop, test, and validate potential AS therapeutics.
Dr. Dindot’s first goal is to reactivate paternal UBE3A expression via an antisense oligonucleotide (ASO) targeting UBE3A-AS. Once that is complete, the next step is to determine which AS symptoms an ASO may improve, and how that is impacted at different developmental ages. The study will examine seizure and brain wave activity, gait and motor coordination, learning and memory, communication, and sleep patterns.
Dr. Dindot’s second goal under this grant is to improve the genome assembly, annotation, and characterization of the pig Prader-Willi syndrome/Angelman syndrome imprinted domain and determine if the CRISPR/cas9 deletion of UBE3A created any off-target mutations.
Results from this study are expected to accelerate translational research in Angelman syndrome and assess the clinical benefit of therapies aimed at reactivating expression of the paternal UBE3A allele. The grant runs from Nov 1. 2019 – Oct. 31, 2023.