Targeting the orexin system to treat Prader-Willi syndrome associated hyperphagia

Funding Summary

One effect of the lack of Magel2 in PWS is lower production of a brain neurotransmitter called orexin. Orexin is key to regulating a number of physiological processes, including hunger and physical activity, and we hypothesize that the obesity and related metabolic function symptoms seen in PWS is linked to a reduction in the levels of orexin in the brain, and medications that enhance orexin signaling may reverse this dysfunction and reduce problematic behaviors. This project will use brain mapping techniques to investigate the extent to which a reduction of brain orexin in laboratory mice lacking Magel2 leads to an alteration to brain function, and test whether novel medications that can boost orexin signaling can reduce the obesity-related behaviors in these same laboratory mice. These experiments will greatly enhance our understanding of the changes in the brain that lead to extreme hunger and resulting behavioral problems in PWS, paving the way for further research. More importantly, if successful these experiments could catalyze the clinical development of much need therapies for PWS.

Dr. Theresa Strong, Director of Research Programs, shares details on this project in this short video clip. 

Lay Abstract

Prader-Willi syndrome (PWS) is a complex and challenging genetic disorder that occurs in approximately one out of every 15,000 births. While PWS may present with a range of symptoms, it is recognized as the most common genetic cause of life-threatening childhood obesity. In newborns symptoms include weak muscles, low levels of feeding and slower development. In childhood, individuals with PWS typically develop a constant extreme hunger, also known as hyperphagia, which can lead to obesity and related metabolic disorders, including type 2 diabetes. The hunger experienced by individuals with PWS can become so intense that it leads to problematic food-related behaviors including persistent food-seeking, consuming non-food items and searching for food outside the home. Controlling these behaviors is complex, and caregivers may need to create physical barriers to food storage and limit exposure to situations where food may be freely available, such as family gatherings. There is currently no cure for PWS and caregivers consistency report that the extreme food-seeking and related problematic behaviors remains a primary unmet medical need for PWS. Highlighting the difficulty in developing such a treatment was the recent finding by an FDA committee that there is not substantial evidence to recommend a new therapy, carbetocin, be used to treat PWS-associated hyperphagia. At the genetic level, PWS results from inappropriate silencing to a variable number of genes on a specific portion of the human genome. The variability and severity of symptom presentation is linked to which genes on this portion undergo the silencing process. Molecular research has linked the metabolic dysfunction that is so prevalent in PWS with a lack of expression of a specific gene called Magel2. One effect of the lack of Magel2 is lower production of a brain neurotransmitter called orexin. Orexin is key to regulating a number of physiological processes, including hunger and physical activity. I hypothesize that the obesity and related metabolic function symptoms that emerge in individuals with PWS is linked to a reduction in the levels of orexin in the brain. I further hypothesize medications that enhance orexin signaling will reverse this dysfunction and therefore reduce many of the problematic behaviors that affect patients and their families. I propose using brain mapping techniques to investigate the extent to which a reduction of brain orexin in laboratory mice that do not express the gene Magel2 leads to an alteration to brain function. In addition, I will test whether novel medications that can boost orexin signaling can reduce the obesity-related behaviors in these same laboratory mice. These experiments will greatly enhance our understanding of the changes in the brain that lead to extreme hunger and resulting behavioral problems in PWS, paving the way for further research. More importantly, if successful these experiments could catalyze the clinical development of much need therapies for PWS providing an enhanced quality of life for people with PWS and their families for years to come.