Welcome to an inside look at some of the impactful research FPWR is supporting to improve the lives of individuals with Prader-Willi syndrome (PWS). In this interview, four of our dedicated research team members—Theresa Strong, Marc Ridilla, Lisa Burnett, and Caroline Vrana-Diaz—share updates on a few of the key initiatives they’ve been advancing this year.
While this conversation only covers a small portion of our work, it offers a glimpse into the meaningful progress made possible through your support.
Let’s explore some of the key initiatives discussed during this insightful interview and see how FPWR is advancing Prader-Willi syndrome research. Watch the full recording from our 2024 Annual Family Conference, or read the key highlights shared below.
What We Learned from PATH for PWS
Q: FPWR recently completed a 4-year study called Path for PWS through the Global Prader-Willi Syndrome Registry. Data from the study has been instrumental in Soleno’s conversations with the FDA. Tell us a bit about what we have learned from PATH for PWS.
Theresa Strong: "First, I want to thank the families who were participants in the PATH for PWS study and encourage everyone to join the Registry; we always have research happening through the registry and we're constantly pulling data to support PWS clinical trials. PATH for PWS was a study we ran through the Global PWS Registry. Families completed surveys every 6 months for four years and recorded any serious medical events that occurred. More than 600 families participated, and almost everybody participated for the full four years, which is a testament to the dedication of our families.
Through this study, we wanted to learn what was sending people with PWS to an acute care clinic and/or hospital. More than 800 medical events were recorded during the four years of the study. Behavior and mental health problems were the number one issue that sent our kids to an ER. Second to this were infections, seizures, and GI problems. We know our kids tend to get backed up (constipated) but now we also know that this is commonly leading to hospital visits. Having this new information will help us prioritize how we fund research so we can continue to support research that has the biggest impact on our community."
The Role of Biobanks in Research
Q: FPWR has partnered with CombinedBrain to collect blood and urine samples for our PWS and SYS biobanks. How have those samples been used to date and how do you see them advancing research in the future?
Theresa Strong: Currently, most PWS clinical trials require caregivers to complete surveys to measure the drug’s efficacy. Surveys can be subjective, and how you answer one on any given day may vary. Ideally, we would like to be able to look at a person’s blood to see if a drug is working. If you can draw blood and say, ‘Oh, this drug is working,' we wouldn’t need as many participants for each clinical trial.
A biobank is the first step to finding biomarkers for hyperphagia. With a biobank, we will be able to look at many blood samples from people with PWS and compare them to typical samples. In addition to developing a blood-based biomarker, new stem cells have been created from samples donated to our biobank and are now being used by researchers at Columbia and other institutions to better understand cellular changes in PWS.
VNS4PWS: A Game-Changing Clinical Trial
Q: FPWR is conducting a clinical trial called VNS4PWS. This study evaluates the effectiveness of wearing a VNS device for four hours a day on temper outbursts in PWS. It’s unusual for a non-profit to conduct a clinical trial. Can you share the background that led FPWR to run this study?
Lisa Burnett: There are not necessarily the same regulatory incentives in the device industry as there are in the drug industry that would spur development for rare diseases. That left us lacking an industry sponsor, even after there were two pilot studies with really exciting data. The needed next step was to run a larger confirmatory study, which necessitates large numbers of volunteers. To get large numbers in a rare disorder, you really need to be working across multiple clinical sites, and that rules out your typical single-center, academic investigator-initiated study. So then you start looking around the room; there's not much other people left. At this point, if we didn't do it, no one else would, and we wanted to see this get done! This project has not been a light undertaking! This is the first large-scale trial that FPWR has conducted. In fact, it might be the first interventional clinical trial that a nonprofit has actually ever sponsored and run itself, so this is a big deal.
The Grant Review Process: What Makes a Strong Proposal?
Q: FPWR reviews grant applications two times a year and selects about 20 grants annually for funding. What makes you 'swipe right’ when reviewing a grant?
Theresa Strong: Grants are selected for a combination of reasons. The work has to be scientifically excellent but also has to be important to our PWS and SYS communities. The project has to be feasible to do, and it needs a good group of researchers behind it. In order to ensure a project meets these criteria, we have both scientific reviewers and advocate reviewers (typically parents from our community), and that combination assures that the science is good but also that it is an important topic for our kids.
As you might imagine, our grant program funds everything from very basic science, for example, what do the genes in the PWS region do, to clinical trials. In fact, the first DCCR study in PWS performed by Dr. Kimonis came through our grant program—and fortunately we funded it!
It is challenging sometimes to prioritize our funding. How do you prioritize a clinical trial, for example, against a project looking at snoRNAs? We want projects that are going to advance the field, and we want a balanced portfolio that includes basic science because you have to understand what's going on in PWS if you want to treat it effectively. But we also need shorter-term solutions, so also fund clinical trials and studies about clinical care—our goal is to balance that.
Favorite FPWR Projects: A Tough Choice
Q: What are one or two of your favorite projects of all time?
Theresa Strong: This is tough. We've funded a couple of hundred projects now, and there are many that are near and dear to my heart. We have funded some really interesting gene activation studies. Genetic therapy is still off in the distance to some degree, but it offers the possibility of being a transformative therapy because it could address everything at once. So, I like the gene therapy projects, but I also like the clinical projects, and I really like the basic science projects too.
While not a grant, the Global PWS Registry has been critical to the development of DCCR and improving how we care for people with PWS. For example, a recent paper from the registry shows us that babies with G tubes have more than 25 times more complications than babies with NG tubes. A group of PWS-CLIC clinicians have now published that information, and it should support it becoming more common for NICU doctors to use the NG tube. To be clear, the G-tube is needed sometimes, but this paper will help make sure that NG tubes are used when they can be used and that G-tubes are not overused.
Developing a High-Throughput Screen for Drug Testing
Q: FPWR has been working on developing a high-throughput screen for some time. Explain to us what a high-throughput screen is and why we need this resource for the PWS research community.
Marc Ridilla: Developing a high-throughput screen has been a high priority for me since I started with FPWR. When we say 'screen,’ we mean that we want to repeat an experiment (tens of thousands of times), with the only difference from experiment to experiment being the drug that's added to the cells. To do this in an automated fashion, you have to choose a limited amount of things to be measured.
It requires a particular kind of scientist who knows how to develop these tests and make sure that when they repeat the experiment over and over, they're getting very consistent results. You want a really small standard deviation so you can detect even a small change and make sure that you're correctly identifying the drugs that are making a difference.
We have chosen a handful of characteristics that seem to be unique to PWS cells that we think have the highest potential to be adapted to screening, and we're working with researchers to get set up to do this screen. We expect that we will start testing the drugs next year. There are currently around 20,000 FDA-approved drugs. These are the compounds we plan to screen first. If the drug makes the cells better or worse, we will need to perform additional tests to better understand why that drug is having that effect. The benefit of starting with FDA-approved drugs is that when we are ready to move into humans, the research will be able to advance faster.
The CLIC Database: Expanding Clinical Insights
Q: FPWR has been working with a group of PWS clinicians as part of the Clinical Investigative Collaborative to establish a database that will collect clinician-entered data. How will this new database be used, and how does it complement the data we have collected in the PWS registry?
Caroline Vrana-Diaz: While the Global PWS Registry collects and stores parent-reported data, the CLIC database will collect data that is normally collected during clinic visits, such as blood work and lab draws. This will be the first time for the PWS research community that clinician data has been collected and shared, and we will be able to compare the data collected by the clinicians with the data that is shared by parents. We expect the CLIC database to increase diversity as it will be used by multiple clinician sites, each with its own diverse population. Consents for participation have been translated into nine different languages so individuals who are not English speakers can consent to participate.
Advancing Gene Therapy for PWS
Q: Gene therapy has the potential to be transformative as it can correct the underlying genetic cause of PWS. How has gene therapy advanced in the past several years? Are we getting any closer to having gene therapy available?
Theresa Strong: We're getting closer, but there are still many steps to go. I would love to be able to predict how long it will take to make gene therapy available, but over the years I’ve gained a little bit more wisdom, and we really can’t predict when we would be ready to go into the clinic. At this point, there are many different approaches that are being evaluated. We have Marnie Blewitt, whom we have funded a couple of times; she's looking at a protein, SMCHD1, that regulates the PWS region. Targeting a protein might be a really nice way to do gene activation because you could potentially use a drug to target that protein. It’s gene therapy because it would turn the genes in the PWS region on, but it's not sticking a virus into your brain. I'm not necessarily opposed to delivering a virus into the brain—I've made viruses that go into people's brains. It can be done, and it can be done safely, but it's not something you want to jump to until you're really confident that it's going to have a beneficial effect. Dr. Blewitt’s work is a nice example of our funding model. We provided Dr. Blewitt with two rounds of grant funding, totaling a couple of hundred thousand dollars, and recently, she just received a $5M grant from another funder to further develop that approach in PWS.
Additionally, there are CRISPR approaches, which are really attractive. We may be able to use CRISPR techniques to activate the PWS genes. Then there are small molecules, drugs, that might turn the PWS region on. So currently, all of these approaches are being evaluated in PWS cells to see how well they may turn the genes on, do they turn other genes on, whether there are any bad effects from them, and other important research questions. Eventually, one of these approaches will be identified as the preferred method. I don't know which one it will be yet, but they're all being vetted. Then they will all need to be tested on a mouse model of PWS and/or a larger animal model before it can be tested in humans.
A Step Forward for Hyperphagia Treatment: Is Theresa Ready to Retire?
Q: We may have our first approved treatment for hyperphagia here at the end of the year. Theresa, are you considering retiring?
Theresa Strong: Don't tempt me! No. I feel like we have a lot of work left to do. It would be great to have a new therapy, and DCCR will potentially be a great tool in the toolbox, but we have a lot of additional work to do before our kids—all of our kids—can have the full, independent life that we want for them.
Support the Research That Changes Lives
Your support fuels projects like these, advancing care and improving the quality of life for individuals with PWS. Join the Global PWS Registry or donate today to be part of this important work.
