Pig Models of Prader-Willi Syndrome for Pathophysiologic and Therapeutic Interventions

Overcoming the strong drive to overeat and obesity with negative impacts on life expectancy and life quality is of upmost and crucial importance for individuals with Prader-Willi syndrome (PWS) and their families. Despite advances in understanding the genetic causes of PWS and the establishment of different mouse models that mimic some clinical components, the actual cause of PWS is not known and no animal model exists with the equivalent overeating and obesity of PWS. The minipig is a large mammal with a similar body and organ size and physiology to human. Further, many human diseases are clinically similar in the pig including for “metabolic disorder” (i.e., obesity, diabetes, and atherosclerosis). In our recent work, we have established for the first time a minipig model of PWS as well as normal “carrier” animals that will be used in this project for breeding to generate a larger number of PWS minipigs for experimental study. Second, this project will provide in depth clinical and neurobehavioral characterization of the PWS minipigs that we predict will display the overeating, obesity, and other clinical features of PWS. Indeed, preliminary analyses indicate mild failure-to-thrive with growth retardation and episodes of hypoglycemia in newborns, as found in human. Third, in this project we will assess the genetic pathways that lead to the clinical features of PWS. The successful outcome of this work will provide the foundation that is critical for future in depth dietary, pathological, neuroimaging, behavioral, and molecular studies that will lead to an understanding of exactly how the PWS genes control how much is eaten and/or how the process of eating at the end of a meal is stopped (i.e., satiety), how that energy is excessively stored and results in obesity, and the basis of disordered body composition (increased fat tissue and decreased muscle mass) even in the absence of excess eating. Our pig models of PWS, expected to include hyperphagia, obesity, behavioral problems, scoliosis, and other clinical features, will provide a pre-clinical large animal model for the future development and/or testing of therapeutic approaches, whether these involve dietary, surgical, pharmacological, genetic, stem cell, and/or neural transplantation approaches. Consequently, the proposed project will greatly benefit PWS research by providing an essential means for understanding the clinical basis including hyperphagia and obesity and for establishing new therapies.

Research Outcomes: Public Summary

This project’s goal was to generate a novel animal model for Prader-Willi syndrome (PWS), in the hope of understanding how PWS genes control how much we eat to explain overeating (hyperphagia) and how storage of excess energy results in obesity, among other clinical features. Molecular genetics and reproductive medicine techniques were used to generate a pig model of PWS, with the resulting study animals midway in size between a domestic pig (very large; mother) and smaller Yucatan minipig (still quite big; father). The Yucatan minipig was predicted to provide a good animal model, as it has a similar overall body and organ size to an adult human with a very similar diet and physiology. This is especially true for what is known as metabolic disorder, featuring obesity, diabetes, and atherosclerosis (excess fatty deposits on the inner walls of arteries, leading to increased risk for heart attacks), where pigs are the best animal models to study these human diseases. In particular, prior to this study the use of mice as animal models has not been all that successful for establishing a PWS animal model with the expected clinical characteristics. We succeeded in the major goals of the funded study, generating 3 founder pigs with mutations that are associated with PWS. One founder, a male PWS pig, had the mutation on both chromosomes (as for humans, one copy of each chromosome is inherited from the father and one from the mother) and displayed some of the clinical features of PWS, including reduced growth after birth, episodes of poor blood sugar control, a sudden increase in eating and weight at several months of age (controlled by reducing and controlling the calory intake), severe scoliosis as an adult, and clinical complications of anesthesia including temperature control and blood sugar. A second male founder pig had the mutation but only in half (50%) of his cells, so although he has some clinical features – such as the same overeating-weight problem – these are milder and less frequent than his fully-affected brother. Finally, a clinically normal female founder pig had a mutation but in a silent state; such a “carrier” female pig could pass the mutation to her male offspring (they will be clinically normal also) but these “carrier” male offspring will then have half his offspring (those that inherit the mutation) to develop the clinical features of PWS (as for the first male founder pig). The establishment of these 3 pig models of PWS allows for the future development of therapeutic approaches, provides a model for development of pure minipig PWS models, and sets the foundation for future studies to gain a better understanding of feeding behavior and body composition in humans.