Interview with the FPWR Research Team [2019 CONFERENCE VIDEO]

In this 57- minute video, FPWR Executive Director Susan Hedstrom moderates as the FPWR research team provides an update on PWS research, achievements to date, and what we are doing to develop treatments for our loved ones with PWS. This session includes Q and A with conference attendees. Panelists include research team members Theresa Strong, Nathalie Kayadjanian, and Lauren Schwartz Roth and FPWR CEO John Walter. Click below to watch the video, or scroll down to read a transcript of the session.

 

Q: FPWR has invested more than $12 million into PWS research. Much of this has been through our grants program. Can you give us an example of how the grant program is yielding some results for us?

Theresa Strong:           

The grants program has been our ‘bread and butter’ since we began. This is a competitive grant program where twice a year, we ask the scientific community to bring us their best ideas. Scientists are thinking about these things all the time and they're in a really good position to understand how to move the field forward. We have scientists review and parents review, so that we get the best science that's also relevant to families, and support that. Some of you have participated in the review process. A very broad portfolio of projects  come out of the grant program, and they were reflected in the day and a half of scientific presentations at this year’s PWS Research Symposium. I would say probably 80 to 90% of what was presented at the Research Symposium was funded by FPWR.

The grant program includes everything from really understanding the genetics of PWS to clinical trials all the way through and through. A few specific examples... If you donated in 2011 or 2012, your funds went towards the first clinical trial of diazoxide, the DCCR molecule, and it was the success of that trial that allowed a pharmaceutical company to come in and pick that up and now, they're now funding the phase 3 DESTINY-PWS trial. If you provided funding in the 2013 range, some of the studies that we supported then were the genetic therapy studies, which have shown promise in mouse models and are advancing towards clinical trials. You have funded new collaborations between some of our investigators. All of the studies, for example, that use dental pulp STEM cells derived from teeth were FPWR funded studies, and those have really gone a long way to helping us understand the molecular changes between PWS and typically developing individuals.         

Q: The first gene therapies for rare disorders have recently been approved in just the past couple of years. These therapies have cured a genetic cause of blindness as well as treated spinal muscular atrophy, which is the leading genetic cause of infant mortality. What are the opportunities for developing a gene therapy treatment for PWS?

TS:                              

So we talked a fair bit about this yesterday. PWS is complicated. So those specific examples, spinal muscular atrophy and blindness, are caused by a single gene. You just replace the protein. It's not easy, but it's sort of a simple problem. PWS is much more complicated because we're dealing with several genes and several RNAs. I believe the gene activation approach, where we're trying to turn on the existing chromosome 15 material that is derived from mom's chromosome  in every individual with PWS but silenced, is a good way to progress for us. With the genetics therapy workshop that we just had, we will put together a road map to try to move that work forward as quickly as we can.

Q:  It has taken several years, but the Global Prader-Willi Syndrome Registry now has nearly 2000 participants enrolled. Why is it so important for people to participate in the Registry?

TS:                              

As we've tried to emphasize, in order for us to understand the incidence of all of the symptoms that occur in PWS and the natural course of the disease we need to have long-term natural history data. Its critical for us to be able to see if any of these new interventions are actually impacting the end result in our kids. We've also used the Registry in collaboration with LEVO therapeutics to develop a new anxiety measure that is now being used in clinical trials. We continue to add new surveys which is why it's so important for you to come back to the registry and continue to complete, and update surveys. If you see in the clinical trials alert that we have a new survey, your participation is really important. Your participation is supporting the clinical trials that are ongoing, and also to helping us understand what problems your kids are having, so that we can be proactive in trying to help the clinicians  study areas that appear to be popping up or develop standards of care that will help our kids have the best outcome possible.        

Q: FPWR has recently begun investing in small pharmaceutical companies in the beginning stages of drug development. Could you tell us a little bit, John, about the strategy and how it will accelerate our work towards treatments for PWS?

John Walter:                

For a long time, our Foundation has been funding bright ideas in labs. And we've come a long way! Now we have several active clinical trials recruiting patients for potential treatments. So the idea with venture philanthropy is to bridge a bright idea in a lab and bring it forward to a clinical trial. This process can take a fair bit of time and we want to speed it up. We've attracted a lot of interest in the PWS space and we now have many companies coming to us to tap into our expertise. The thought here is to look at the entire continuum of drug development, from preclinical trial work to phase one, phase two, and phase three trials. And where can the foundation help financially, and intellectually, to help take some of these early companies that are looking at our space and potentially move  forward trials and invest in them. Invest in them financially and lend our name to the fact that our scientific advisory board has reviewed the science there. Our investment committee has looked at the companies and the structures of those companies and said, this is a good bet. And the goal there really is to help bring larger dollars to bear for these companies and accelerate their work.

Our board just approved this approach to investing. And this summer  we invested in two companies. The first one we have talked about, it's a company called Inversago. This company has a reformulated compound that had some issues earlier but they've reformulated so that it doesn't cross the blood brain barrier. It targets the endocannabinoid area of the brain, and targets a number of things, such as hyperphagia and behavior, like many of these other trials that are going on. We had invested them once already through our grant program, then they came back to us again, and now we have invested in them again.

The other company, interestingly enough, has been established based on research FPWR originally funded at the Hebrew University. They identified a molecule that showed propensity for enhancing bone strength and bone density. They have intellectual property has been licensed to a company called Beryl Therapeutics. They approached us about joining an early friends and family round, to try and move that science forward. We invested $150,000 in that company, which represents 10% of that friends and family round. The goal is help them get the work done to see if there can be the opportunity to prove efficacy.        

Q: So clearly a lot of work has, has gone into play in the last even just five years. We went from having no clinical trials to now having three that are actively or five actively recruiting drug trials and more coming. So what do you think has been one of the most significant factors in bringing clinical trials to PWS? And maybe you could talk a little bit about FPWRs role in that.

Nathalie Kayadjanian:                              

I think one important thing is that we have developed a research ready community. Often companies are interested in rare diseases as a ‘proof of concept, before then going on to more common indications, such as obesity. Companies are looking at rare diseases, like PWS, and they not only want to know if the science suggests their drug may be helpful in that disorder, but also what tools are available to help them and how strong is the patient community. They want to know how we can help identify patients and whether there is a patient registry. (Our registry currently has nearly 2,000 participants!) That's one of the first things that they, they ask. So all these tools are really important also to attract these companies.

TS:      

I can add that we also are really proactive in engaging the FDA. We are involved in larger efforts by the rare disease and other disease communities that keep us at the forefront of how do you effectively engage the FDA, how do you educate the FDA about the needs of the community? FPWR’s a member of the clinical trials transformation initiative which is a public-private partnership between the FDA and Duke University that is charged with making clinical trials more efficient. Also, Jessica Bohonowych and I have both been involved in some projects through that effort, how to best engage patient groups. I was in a project on using mobile technology in clinical trials and it's an opportunity that is a partnership of academic groups, many of the large pharmaceutical companies and patient groups so it's a great opportunity for networking. I'm also on the patient engagement collaborative at the FDA, which is a three year appointment. It's a fantastic group of advocates that work towards improving communication between the FDA and the patient community. And just being a part of that I go to DC twice a year and we have i-person meetings and it's an opportunity to learn about the FDA. I've been engaging the FDA for many years now and it's kind of a Behemoth so even knowing who you should be talking to takes a few years to figure out. So just having that direct contact and someone at the FDA that you can pick up the phone and ask ‘how do I navigate this’ is just fantastic. So I think being proactive and being part of these groups is really important to make sure that we're doing everything we can to be advancing the efforts of our community.

JW:                             

I'd add one other thing. One of the things that FPWR does really well is proactively connecting the dots. So being aware of what companies are doing, that might have overlap into the PWS space. And I'll give you a specific example of that. This summer I was up in Boston and was talking to someone and they mentioned to me that there was this company that they had come across that was developing a blood thinner, so a competitive product for products like perhaps Warfarin or Eliquis that you might be familiar with. This blood thinner will be a second generation that has less of the side effects. And I had an early conversation with the company and said, look, are you aware of the, of the thrombosis issues that exist in PWS? Would you have any interest in doing that? And so of course after that conversation was over, I quickly knew I needed to connect them with Theresa to have a more in depth scientific discussion to talk specifically about the underlying issues of thrombosis and PWS. But the CEO of that company came to the consortium meeting this Wednesday to try and learn more about what we're doing and what kind of resources we had to help them, and potentially they might have an interest looking at PWS and addressing those thrombotic issues.                            

Q: So our next question is going to go out to our mental health expert. Lauren, we know that there are many people who have PWS who struggle with mental health. What are we doing to understand why our loved ones are at a higher risk and what are we doing to help them?

Dr. Lauren Schwartz:   

One of the things that I’ve been interested in for many years, given all of the challenges that our kids can have, is really understanding some of the early signs and predictors of mental health challenges. And if we can understand the early signs and symptoms, we might be able to do more to intervene earlier on. Generally, in mental health, if you diagnose and treat early, you have a much better outcome and you might even be able to prevent some more severe symptoms. So that's something I'm very interested in.

We have funded several grants over the last few years that have been looking at sensory, cognitive and social challenges to see if that may help us understand the trajectory towards mental health problems. We're also just funded an MRI study by Stuart Einfeld and Lauren Rice at the University of Sydney who do lots of great research. They're also doing the mindfulness study. And they're interested in looking at GABA in the brains of people with Prader-Willi. And GABA is a chemical in the brain that is linked to emotional challenges in several different conditions prior to really autism and some other conditions as well. And people with PWS tend to have lower levels of this important brain chemical. So they are looking at the brains of people with Prader-Willi and they're going to be giving them a medication that is supposed to change levels of GABA and they'll see if this can help sort of normalize those levels in the brain. And if that happens, then they'll go to the next step to see if doing a clinical trial in that area would be helpful. So I think there's a lot of interesting things going on in that area.

We're also starting to look at ways of talking with families and Prader-Willi behavior experts about their experiences struggling with mental health challenges. And again, what are some of the early signs and symptoms that parents and caregivers recognize? What kinds of treatments have been helpful so that we can create a framework to help parents prepare and be informed of these things if they do become an issue down the road.

We also have two trials going on right now that are recruiting participants. One is for guanfacine, to see if it's helpful for aggression and impulsivity and other behaviors. Another study is taking place at the University of Sydney on mindfulness, looking at this very specific intervention for people with intellectual disability in Prader-Willi, to see if they can learn to use these techniques to control their anger and other symptoms as well. So there are things going on right now that you could possibly participate in that could be helpful for your children.          

There's also another study that just started. Dr. Jan Forrester who is a psychiatrist whose worked in Prader-Willi for decades. She's a real expert in the area, has become very interested in family stress for people who are parenting a child with Prader-Willi. And in particular she feels like the dads have been really neglected. And so she has developed a study to look at a very specific intervention called ACT, which is acceptance and commitment therapy. It's kind of a version of cognitive behavioral therapy and mindfulness for dads and who have an adolescent with Prader-Willi. And it's also a virtual online kind of Skype intervention, it's four sessions. And so she's recruiting currently for that study, and we're really excited to be having some focus on the dads.

If you want more information, if you go to fpwr.org we have a menu items called clinical trials. All of the trials are listed there, both the drug trials as well as intervention trials. If you scroll through, you're going to see a nice list of opportunities that are enrolling patients currently.

Q: This final question goes to every member on our team before we go to the audience. What is the next three to five years look like in research?

TS:                              

Busy! If the last three to five years is any indication, the next 3-5 years will absolutely be busy and I hope transformational! I think there's a lot of things on the horizon that really have promise in the next few years. I mean all the way from babies, right? So newborn screening: we expect in five years to be advancing to the point that we're diagnosing every baby at birth and getting them right into a doctor. If you diagnose every baby at birth, you can get them right on growth hormone and give them the best possible start. These drugs that are in clinical trials now I think will, I mean in my wonderful imagining of the world, we'll have many options with new drugs that are approved. And so we'll be able to find the drug that works best for our child and the particular ‘brand’ of PWS that they have. And then we'll be moving forward and hopefully making fantastic advances in getting at the root cause of PWS and maybe, you know, moving genetic therapies ahead. So that's a couple of things.

NK:                              

We are developing a pre-clinical network to improve mouse models which are used in preclinical stages. And why do we do this? Because we want to de-risk drug development. This will improve how we do research and will improve our ability to develop drugs, specific drugs for PWS.  It will be advantageous to have good cellular and animal models where we can directly test drugs against all the major symptoms of PWS.

LS:                               

Well it's my hope that within the next three to five years we will have some treatments that have been studied and are effective for the mental health challenges that our children experience, both medication as well as some non-medication approaches and also some interventions out there that are accessible to families to help reduce stress so that we can have renewed resources to keep going, to take care of our children and, keep trying to find more treatments.

JW:                             

I like to really boil things down in ways that we can understand them. The way that I look at what we're doing now and, and where we are is really straight forward. Our research programs are really doing two things: We're looking for solutions now. How can we bring forward therapeutics to address some of the hallmark symptoms of Prader-Willi syndrome? So hyperphagia, behavior, etcetera. And the good news is that those are being addressed. So within the next three to five years, I think we will have at least one, possibly two, and hopefully three approved drugs for hyperphagia and behavior or various aspects of behavior. We all know that the issue of Prader-Willi syndrome is a spectrum disorder. So to have the option of having several drugs that address the same symptom is wonderful.

The other piece of this is the hope for the future and the hope for the future which could be measures in the area of genetics for prior Willi syndrome. In the next three to five years, I'm optimistic that we will begin to see if we can put forward work that will allow us to potentially do partially curative treatments in the area of genetics or Prader-Willi syndrome.  If we don't try, it won’t happen. If you listen to Stormy Chamberlain and Jim Resnick talk about some of the things they're doing, there are opportunities there where we can do proof of concept. And the only thing that stands between us and doing that is the dollars to fund the work. So I think a big part of this is really when you go back to your communities, talk to them and your friends and families, and we're making amazing progress. We couldn't do it without you. And we're not going to make these achievements in that three to five window without more help from you.                          

 

Questions From the Audience

 

Participant: I have a specific question on the guanfacine trial. I'm just curious, what's the purpose of the trial right now? We can go see our doctor, we can get it prescribed already. What would be the benefits of going through their study rather than just going directly through our doctor?

TS:                              

The purpose of the study is to understand in a controlled setting how well guanfacine works. So we all hear, ‘oh, this works.’ It's the same thing that we do with supplements, right? One family feels like it works, one family feels like it doesn't. But if you do a trial and you have the same physician looking across all of the patients, A) you get a real handle on what dose and how you should administer it and B) you get a real handle on the safety concerns and C) what percent of kids are going to find it effective. And if there's certain genetic subtypes that are more effective than the others, or other characteristics that are going to distinguish responders from non-responders, you can pick that up. So a study like this makes it more efficient to actually know what to do for any individual child.

LS:                               

Just going to add that a lot of times these medications are tried and we feel like the individual seems better, but this was going on and this was going on, so we're not really sure whether it was the medication or something else. In a trial where they're using objective outcome measures that are being administered by people who don't know who's on drug and who's not on drug, we can get some real objective information about is there truly a change in anxiety or aggressive behavior, or impulsivity. So a study helps us make decisions about whether that's the right medication for our child.

Susan Hedstrom:                              

Medications are highly individualistic from child to child and I think when you start getting into psychiatric medications it gets even more challenging. And not all of our psychiatrists have a strong experience with Prader-Willi. They know, autism, they know anxiety, they know bipolar or depression, but they don't necessarily understand the full nuance of Prader-Willi. So having a publication that is specific to the Prader-Willi population is incredibly helpful. And I can speak to this with personal experience of going to a psychiatrist and saying, I need to try a medication for my son. And he said, well we should try this one because this drug is good, it's well tolerated in the general population. But what I knew from having talked to Prader-Willi experts was that that drug with not the best choice for my son, and I did not want to start there. So I needed to have medical literature to bring to my doctor and he was very receptive once I brought him that information. But if I, as a mom, without an MD or a PhD, just walked into his office and said, well, I want this drug, he would have been much less responsive and willing to listen to me. So having this study published is incredibly important for us so that we can advocate for our children with our doctors.

Participant: This question is for Theresa. You spoke a lot yesterday about some of the research that we're doing, the Foundation's doing, on two genes in specific, which were Magel2 and Snord116. And I'm hoping that you can explain a little bit why the Foundation is looking at those two genes and what implications that would have if the research, and the correction of those two genes would have on the syndrome?

TS:                              

Well, that's what we're trying to figure out. We know both of those genes are really important. Loss of those genes is critical for developing the symptoms that we associate with PWS. So, we know Snord116 because there are about five really rare patients that keep all the other genes but just are missing Snord116 and they have most of the symptoms of PWS. So we know that area is really important. So we're trying to figure out what does the Snord116 do? And we know if Magel2 is mutated, you also get many symptoms that are very similar to a PWS. So that is clearly an important gene as well. What we don't know, and what we will hopefully be able to figure out with the animals that we’re making through the preclinical network, is if we took a background of PWS, like a large deletion like many of our kids have, and we put just Magel2 back on that background, which is a relatively small gene, you could do sort of straight up gene therapy with that, would it improve the situation well enough where that actually might be a good treatment? So we haven't been able to do that before, but we're developing animal models and the cellular models to go ahead and do that kind of thing. So that area is so complex. There's clearly an interplay between all of those genes and we have to understand that a little bit better. But in the meantime, we can look at the specific genes. Does that answer the question?

Participant: My question relates to the last point that John made about research dollars. So we held our first One Small Step event, just before my daughter turned one and I found she's now five. And I find that it gets a little bit more difficult year over a year because you're generally engaging the same people for support in fundraising. So I was just wondering if you had any tips on renewing interest or enthusiasm, and or I guess broadening the reach of fundraising when you're kind of constantly doing it?

SH:                              

You have a very excellent question! I think a lot of people have the same one. We're going to go into this in a little bit more depth after the close of this session and then in our next panel. But I will say that we all get busy and we feel like we can't ask again of our donors sometimes, but if you don't ask, you won't get anything. So, doing something that you're comfortable with, or even pushing your envelope a little bit. Setting up a Facebook fundraiser is a really easy task. It's an easy ask and people give because they want to support you. Your friends want to support you, but they don't know how, so if you give them an opportunity and you say, this would be meaningful. They often will reciprocate; they will show that they want to. They want to do something for you.

Participant: Is there action that's happening from FPWR or other organizations to try and revise the FDA approval so that we can get Growth Hormone approved for what our kids need it for, not just during their adolescents but for their adult lives as well?

TS:                              

Absolutely. So this has been a real focus of mine over the last year, year and a half. And it's a hard problem, and you wouldn't think it would be. There are multiple small trials that have been published that all show benefits for GH in adults. And so it kind of, it seems like a no brainer to us. My son's 25 and we went through the same thing. He got kicked off and it took us about a year and a half to get him back on. So FPWR is doing several things. We are engaged with the large pharmaceutical companies, and working with them and encouraging them to run a trial. The challenge as a advocacy organization, is that we can't go to the FDA and say, you got to approve this. It has to be a sponsor. So it has to be a drug company. So we are working with the large pharmaceutical drug companies to encourage them to do that and do a clinical trial or just put together the information that they need to get an FDA approval. We are working with smaller companies that are looking to break into the market and maybe do a clinical trial in adults. The third thing we are doing is we have funded Laura Degraff who's in Europe and, she has put together 10 clinical sites and we're funding the actual clinical trial in adults. However, to do a large trial with 100 individuals over the course of a year is about a $1M in drug costs. We can't afford that so its taken a long time, but a company has finally agreed to donate the drug and placebo for that trial. So we've got three irons in the fire, and we're working hard on all of them. And, it's taken a lot longer than we'd like, but it's moving, hopefully ahead.

Participant: Is an inherent part of that in order to get that trial to make it a successful trial, having people who are currently on growth hormone agree to go on and potentially not have that drug for a year to see what the effects are of coming off of it?

TS:                              

Well, no, I think what they'll try to do is take people who are not on growth hormone now and put them on, and so there'll be some who don't get drug for six months or a year and then will get drug, and others who get it from the start. But it should not be too hard because the majority of adults are not on growth hormone now, especially in Europe. So there'll be a lot of European sites. They'll also be US sites, but there's several European sites, so they should be able to recruit.

Participant: My question's a little bit broad, but thinking back to several years ago when I first got involved with the Foundation, there were some significant challenges that we were working for, like big meaty challenges. Like there are not enough or no, in some cases, animal models. There was no cell network. We needed collaboration with industry. These are meaty challenges that we've solved over the last several years. What are the meaty challenges for the next five years? I know we talked about what we're hoping and wanting to see, but what are the big things that we need to push through, you know, going forward to make even more progress?

TS:                              

So I'm a geneticist, so I would say understanding how variance in other parts of the genome impact the severity of PWS and now hopefully with new drugs coming on board responsiveness and to those new drugs. So that's what I'd like to sink my teeth into coming ahead.

NK:                              

Maybe I would start first by saying that we've put many things in place but many of them are ongoing and they need to be finalized. We have a strong animal model network. We have good tools. I'm a neuroscientist and I think that is also a very important area to push forward. We’ve seen some really great neurobiologists coming to the field and they are pushing for a better understanding of what circuitry is involved in PWS and fitting in behavior, anxiety, and mental health.

LS:                               

And to add one thing, I don't know if it's super meaty, but it's somewhat meaty, which is also outcome measures and end points. You know, there's a lot of conversation about the hyperphagia questionnaire. It works very well but maybe isn't perfect. And so we are working on developing and considering options and encouraging the development of other ways of assessing important outcomes like hyperphagia, anxiety, even temper outbursts. So continuing to work on developing those outcome measures that can be useful in a clinical trial is a challenge that we are focusing on the next few years. I think will be meaty.

TS:                              

Just one more thing. I think, addressing the cognitive issues in PWS and understanding that there's been so many advances in other intellectual disabilities that I think can be brought to bear on understanding the cognitive disabilities in PWS. That's definitely something that impedes our kids independence. And if there are drug, or non-drug, ways to improve cognition, I think that's definitely something meaty to sink into.

Participant: I didn't go to the conference when my son was born nine years ago, but my husband did and there were 30 people there. So we've definitely been having a moment this weekend of thinking about how much FPWR has grown since we've been in the community. And that's pretty amazing! My question was, speaking on that note, there seems to be a lot of interest in Prader-Willi syndrome from researchers and scientists, which is amazing and it feels like it's growing. So how do you guys as a research team prioritize what projects get funded or what work we actually put the energy and the funds into?

TS:                              

So we spend a lot of time reviewing the landscape and then prioritizing things according to the needs that we hear from all of you. And that we see in our own lives quite frankly. We do have limited funds so we have to consider how we can leverage those funds, what are the ways, the resources that we can develop that many scientists will use? What are the projects that we can fund that will lead to bigger projects that can be funded by pharmaceutical companies or by the NIH? So trying to use these funds wisely, and leverage them as much as we can, is really something that I think we keep in mind all the time.

SH:                              

We also conduct regular meetings with researchers. Just this last Wednesday we held a genetics meeting. It was all inspiring to see the level of expertise in that room. And we shared what do we know? And then we asked what do we need to know and what do we need to do next? So the top experts in the world sat there together and collaborated and put together a list of things that they would prioritize as next steps. We've done that in mental health with a mental health workshop. We've now done this with the genetics meeting and we will continue to have meetings like this annually. So we certainly take in the input from the families as well as the research community to make sure that we're hitting every angle.

JW:                             

And with some risk, I'll use a sports analogy here. We have taken a very methodical peer review approach to reviewing and looking at our research and allowing experts review it. So the hockey analogy goes like this, and the Canadians in the room will appreciate this. In order to win a hockey game, you need 50 to 60 shots on goal. Only three of them have to go in. So one of the things that I want to do going forward is really challenge the research community to say, where can we take some leaps of faith to say, we really need to try this? Because if we are right we could potentially advance some science that we know fundamentally has potential. But if we wait to try and understand the full breadth and full scope of everything, it will take much, much longer. So I'd like this to take some shots on goal, not, not with everything but with some things where we have sort of systematically looked at things and see if we can't get a couple of goals.

 

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Topics: Research

Susan Hedstrom

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Susan Hedstrom is the Executive Director for the Foundation for Prader-Willi Research. Passionate about finding treatments for PWS, Susan joined FPWR in 2009 shortly after her son, Jayden, was diagnosed with Prader-Willi Syndrome. Rather than accepting PWS as it has been defined, Susan has chosen to work with a team of pro-active and tireless individuals to accelerate PWS research in order to change the future of PWS. Inspired by her first FPWR conference and the team of researchers that were working to find answers for the syndrome, she joined the FPWR team in 2010 and led the development of the One SMALL Step walk program. Under Susan’s leadership, over $15 million has been raised for PWS related research.

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