This project takes the first steps towards developing a primate (macaque) model of PWS. Animal models of PWS are currently limited and are not able to replicate some important aspects of PWS, such as intellectual disability, as well as behavioral and social impairments. These aspects of PWS may be more effectively studied in a primate model. Our funding will support the generation and characterization of the cell lines needed to establish a primate model of PWS.
Theresa Strong, Director of Research Programs, shares details on this project in this short video clip.
Watch the full webinar describing the 11 research projects funded in this grant cycle here.
Prader-Willi Syndrome (PWS) is a genetic/epigenetic disorder, manifested by infantile hypotonia, intellectual disability, and obesity caused by hyperphagia. Some individuals have a gene deletion at chromosome 15q11-q13, while others exhibit abnormal epigenetic modifications, which are chemical modifications of the genome and play a key role in regulating gene expression, at the locus.
Despite decades of efforts, it remains unclear which specific gene deletions cause PWS and how they result in the phenotypes observed. One major reason is that PWS research has been severely hampered by the lack of bona fide animal models, which are essential for understanding the mechanisms underlying the disease. Although the mouse is the most commonly used animal model, it has limitations for understanding human diseases because of the large physiological and behavioral difference between mice and humans. In fact, current mouse models of PWS that have been generated by knocking out genes located at the PWS region do not show certain phenotypes observed in individuals with PWS (e.g., intellectual disability, or insatiable appetite). To address this issue, we propose to generate non-human primate models of PWS (specifically using the cynomolgus macaque), in which the locus responsible for PWS is edited either genetically or epigenetically.
Why is this research important? Non-human primate models of PWS may exhibit phenotypes not observed in mouse models, since they are more similar to humans. In particular, a macaque model is superior and essential to investigate how abnormal gene expression leads to organ-specific dysfunction, and how defects in neural function affect high-order brain functions involved in appetite control and intellectual ability. Taken together, non-human primate models of PWS (with either gene deletions or abnormal epigenetic modification at the locus) may address the insufficiency of previous animal models, and may allow us to uncover not only how genetic and epigenetic abnormality induces this condition, but also potential treatments for PWS.
If the PWS macaques are generated, we will analyze the phenotypes of these models. In particular, we will focus on PWS phenotypes related to higher-order brain function (e.g., intellectual disability, and insatiable appetite), which have not been observed in mouse models. Next, we will restore the expression of candidate genes to test which genes can rescue PWS phenotypes. This study may allow us to uncover not only which genes and organs are responsible for PWS phenotypes, but also potential treatments for PWS.
Juan Carlos Izpisua Belmonte PhD.
Juan Carlos Izpisua Belmonte PhD.