Prader-Willi Syndrome & Scripps

A hunger for a cure drives promising Prader-Willi investigations at Scripps Research

Between the ages of 2 and 8, children with Prader-Willi Syndrome begin to experience a hunger for food that never goes away for long. It is often so intense that it feels like starvation. This is due to genetic damage on Chromosome 15 and to the abnormally high levels of an appetite-stimulating hormone called ghrelin.

At Scripps Research in Jupiter, Florida, Staff Scientist Cristina Grande, PhD, has spent several years characterizing how the brain controls and regulates appetite in a mouse model for Prader-Willi Syndrome. Her studies lead to a collaboration with the institute’s chemists on a potential medication designed to provide life-changing relief for people born with the genetic disorder.

Many people with Prader-Willi Syndrome report an inability to feel satisfied and full after a meal, and so they keep eating. Unfortunately, all of the ailments associated with overeating, including obesity, diabetes and cardiovascular disease, frequently go hand-in-hand with Prader-Willi Syndrome, and can lead to a shortened lifespan. Significant progress has been made thanks to the generous donations to the Prader-Willi Research Fellowship at Scripps Research, but we are still in need of a cure, Grande says.

“Thanks to gifts made to the Prader-Willi Classic, we identified a new mechanism in the brain that regulates appetite. It can explain the constant hunger associated with Prader-Willi Syndrome,” Grande says. “Based on our findings, chemist at Scripps Research have synthesized a molecule that shows very promising results, not only in suppressing appetite but also in regulating other features characteristic of Prader-Willi Syndrome.”

Other researchers have tried blocking ghrelin signaling in appetite-related nerve cells, expecting it would normalize the desire for food and reverse at least that part of the disease. But the pharmaceutical industry—seeking a blockbuster obesity drug—already tried that without success.

At Scripps Research, studies led initially by metabolic disease expert Roy Smith, PhD, funded in part through the Prader-Willi Classic, showed that ghrelin receptor signaling was more complex than initially understood. On appetite-regulating neurons, he learned, the ghrelin receptor can work as a complex with another receptor, the dopamine D2 receptor.

Working with Scripps Research chemist Ted Kamenecka, PhD, and Grande, then a post-doctoral research fellow, Smith identified a potential drug that effectively hits that complex—in a way that successfully suppresses feeding behavior in mice models of Prader-Willi Syndrome.

The potential drug’s effectiveness extends beyond hunger, reversing abnormal compulsive behaviors also seen in people with Prader-Willi Syndrome. Today, work continues at Scripps Research with support from donations to the Prader-Willi Classic and affected families.

Kamenecka says the team is now working to optimize the drug candidate so that it may be moved to patients in clinical trials.

“Today we have a promising lead drug molecule in hand that we know reduces appetite and other features reminiscent of Prader-Willi Syndrome in animal models of disease,” Kamenecka says. “A team of biologists, chemists and pharmacologists are currently working hard to  optimize the efficacy, safety, and drug-like properties to ensure the very best candidate moves forward.”

“We know how many families are waiting for help in management of Prader-Willi Syndrome,” Grande adds. “These donations propel that work forward.”


A note from the Levine and Wilkinson Families

Our purpose is to raise funds for research so that we can find a cure and effective treatment for Prader-Willi Syndrome, a non-inherited and potentially life threatening genetic disorder. It is a life-long condition that affects appetite, growth, metabolism, cognitive function and behavior. By participating in our golf classic you become our partner in securing a good life for Josi, Harold and others with PWS. The more you do, the more we can do.

Thank you for helping. It’s about our children, what more can we say?

 

Your hosts,

Ronnie and Ira Levine
Jill and Harold Wilkinson