Celebrating Top Members-Project Vote-Getters: Spotlight on Prader-Willi Syndrome

[I've written here about six projects proposed for the American Express Members Project that were in the top 25 by number of votes, but were not selected by the advisory board. To celebrate the efforts of parents who got that vote out, and spotlight some worthwhile charities, I'll be profiling each of the bypassed projects; today's is the third in the series, and you can find the others at the end of this post. Though they're no longer in the contest, I hope you'll consider voting with your pocketbook and making a donation.]

Project Name: Fight Obesity With a Cure for PWS

Popular Vote: The project was #16 in number of votes when the American Express Members Project Top 25 were chosen, with 2,685.

Disability Addressed: Prader-Willi Syndrome. According to Mary Kugler, RN, About.com guide to Rare Diseases, "Prader-Willi syndrome is caused by a genetic disorder of chromosome 15. Prader-Willi occurs in approximately one of every 12,000-15,000 people, in both boys and girls, and in people of all ethnic backgrounds. Although rare, Prader-Willi syndrome is the most common genetic cause of obesity." To hear about the effects from children with the disease and their parents, view the video "Prader-Willi Syndrome."

Achievable Goals: I asked Theresa V. Strong, grants program director for the Foundation for Prader-Willi Research (FPWR), and Craig Polhemus, executive director of the Prader-Willi Syndrome Association (USA), what might have been done with the amounts of money the Members Project is awarding this year, which range from $100,000 to $1.5 million.

Strong's response: "PWS is a complex neurodevelopmental disorder that is characterized by alterations in hypothalamic function, leading to uncontrolled appetite, emotional instability, intellectual disability, and pain insensitivity, among other things. The genetic region responsible for PWS (on chromosome 15) was identified more than 25 years ago, but it’s still not clear exactly how disruption of this region leads to the characteristics of PWS. So there are many potential areas of research that have the potential to impact positively on those with PWS.

"To date, FPWR has used its resources to support 'pilot' research studies, typically consisting of $20,000 - $50,000 per year for up to two years. Since PWS covers a broad range of disciplines (from genetics to hunger and metabolism to neurobiology to behavior), the studies we have supported have come from experts in these areas around the globe. These projects have led, among other things, to the development of a mouse with PWS, which can be used to test new drugs and therapies; a better understanding of the how the 'hunger hormone' ghrelin affects the reward circuits in the brain (abnormally high levels of ghrelin is found in those with PWS); and a study to evaluate behavioral interventions for obsessive compulsive symptoms in PWS.

"Such support has also been used to help young physicians and scientists as they get started in their career studying PWS. So, with additional funds, we could support several new pilot projects using this same approach. Alternatively, a larger amount of funds (over $200,000) would allow scientists to target specific clinical initiatives -- examples might include testing antiobesity drugs in this population, developing well-characterized interventions for behavioral problems and mental illness, or developing a 'biobank' with DNA from individuals and correlating clinical data to share with the research community."

Polhemus's response: "Our maximum grant award is $50,000 each for a two-year period, totaling $100,000 per research project. Research projects of this size commonly lead to nationally and internationally recognized research publications, direct impact on treatment recommendations, and success by families and medical providers who implement those recommendations. But every year we have to turn down so much promising research because funding is lacking. Every single research project we fund produces achievable results (helping either prove or disprove specific theories about obesity, for example), but because PWS is classed as a rare disease, federal and foundation funding is extremely limited. Funding for most research projects are the result of individuals, such as those who took part in the Members Project, who take it upon themselves to raise funds for research to solve the puzzles of PWS and of obesity in the general population."

Current Research: "There is so much exciting research it is hard to know where to start!" reports Polhemus. "No anti-hunger drug has been found to work consistently for those with PWS, so hyperphagia research is a high priority for us. There is current research indicating that eating an extremely large meal early in the day causes a clearly measurable reduction in hunger later on. If we can determine which hormones are causing the reduction in hunger from the large meal, the hope is that these hormones can be combined into a 'cocktail' that could be injected to cause the same reduction in hunger without the excessive caloric intake. Clearly this approach would hold similar promise for other populations at risk of obesity -- and it is the special window of opportunity into how obesity works that the PWS population offers which could bring this result about not just for themselves but potentially for the general population.

"A similar analysis could apply in the case of restricted repetitive behavior, which is extremely common in those with PWS but also reflects issues faced by those with Autism Spectrum Disorders and OCD. We are currently funding a project on the Genetic Underpinnings of Restricted Repetitive Behavior. Though focused specifically on those with PWS because they are a discrete population subject to this problem, scientists are looking to this research to provide insights regarding others who demonstrate such behaviors such as those with Austism Spectrum Disorders or OCD. This could be a major step toward identifying a genetic cause for (or tendency toward) such behavior in the general population."

Adds Strong: "Cutting-edge technology is being used to understand how the loss of genetic material from the PWS region affects the way the cell works. There’s also a significant basic science effort to understand how that region of chromosome normally turns genes on and off -- these are critical questions understanding how our genome works, and is of great interest to geneticists. On a more practical level, ongoing studies are looking at how to reactivate genes in the PWS region. Other studies are looking at why alterations of this region of chromosome 15 are frequently associated with autism. New mouse models are helping to elucidate how changes in the brain result in the anxiety common in PWS, and why there is such a drive to eat in those with PWS."

Potential Impact: "PWS was the first field where imprinted genes were discovered -- where genes from the father function differently than the same genes from the mother," according to Polhemus. "Specifically, PWS is caused by problems in a particular area on chromosome 15, if the chromosome from the father has a deletion or is replaced by a second chromosome 15 from the mother. If the same problem occurs on the chromosome 15 from the mother instead, the outcome is not Prader-Willi syndrome but rather Angelman’s syndrome, which has quite different characteristics. Since then, several other genetic conditions have been traced to imprinted genes -- so the impact of research into PWS has helped many other people as well and has increased our understanding of some important aspects of genetics.

"More specifically, given the current child obesity crisis, PWS offers a window of opportunity for research into the causes of and effective treatments for life-threatening obesity. Those with PWS offer an ideal test population where hyperphagia (uncontrollable hunger), low metabolism (such that those with PWS gain weight on many fewer calories than normal), and propensity for excessive weight gain can be studied with consequent improvements in our understanding of obesity in the general population. These insights are extremely achievable -- and as in the case of imprinting, the impact will go far beyond those with PWS."

"The development of new therapies for PWS might also have a significant impact on cancer," according to Strong. "PWS is caused by 'silencing' of genes in the PWS region of chromosome 15; genes that are supposed to be 'on' are stuck in the 'off' position. One potential therapeutic approach is to design methods to turn the PWS genes 'on' at the DNA level. Development of such technology might also be widely applicable to cancer therapy, since one of the major factors driving cancer formation is the silencing of genes that normally act to keep a cell’s growth in check. In fact, an understanding of gene silencing in PWS provided the basis for understanding gene silencing in cancer."

Personal Appeal: Jessica Howard, who submitted "Fight Obesity With a Cure for PWS" to the Members Project, writes, "Many challenges make life with PWS difficult, but one stands out among the rest. Extreme, constant hunger makes those with PWS feel alone and embarrassed and it can cause them to literally eat themselves to death. Our son is just three years old and does not yet feel the intense hunger (it tends to surface between ages 2 and 6). He is very bright and loving, and has a natural talent for saying 'hi' to people who seem to need cheer. He’s so 'typical' at this stage and knowing the other side of PWS is coming is pure torture.

"The only obstacle keeping him from one day driving a car alone, living in a dorm, working in a typical office, is the real possibility that he will slip up, just once, and eat so much his stomach will rupture. Sadly, many adults with PWS die this way every year. Finding a treatment for this insatiable hunger would set those with PWS free -- free from hunger, free from constantly being watched, free to be normal members of society. Learning what causes this hunger could open many doors to help countless others suffering from obesity."

How to Help: Both PWS (USA) and FPWR accept donations online and have research projects ready to utilize it, Polhemus suggests. "Our Scientific Advisory Board includes more than a dozen internationally acclaimed scientists who collectively have expertise in all aspects of PWS. We have strong connections with virtually all the leading research institutions working on PWS, including member institutions of the NIH-funded Rare Disease Clinical Research Consortium on Angelman, Rett, and Prader-Willi Syndromes and dozens of other leading institutions worldwide. Similarly, FPWR administers an extremely effective research funding process in which leading scientists as well as parents of children affected by PWS review the scientific merit as well as the practical significance of proposed research. The PWS community is an amazingly dedicated, productive group of parents, scientists, and professionals dedicated to improving the lives of those with PWS and others suffering from hyperphagia or obesity."

From the Prader-Willi Association (USA) site, you can donate money or find other ways to give. The Foundation for Prader-Willi Research also offers an opportunity to donate on its site.

Previous spotlights:

• Eosiniphilic Esophagitis
• Fragile X Syndrome