In this 1 hour and 2‑minute video, Dr. Theresa Strong, FWPR’s director of research programs, shares highlights from the 2021 PWS Research Symposium. The session includes Q&A from participants in the 2021 FPWR Virtual Conference.
Click below to watch the video. If you're short on time, scroll down for timestamps to find the portions you're most interested in.
Presentation Summary With Timestamps
- Susan Hedstrom introduces Dr. Theresa Strong, director of research programs, an accomplished geneticist, and a mother to a young adult with PWS.
1:22 Theresa Strong Presents Highlights from the virtual PWS Research Symposium
- Symposium included 2 days of talks, 21 talks in total, including general sessions and then concurrent sessions with a clinical track and a molecular biology track.
- Also had a virtual poster session where 16 scientists presented their work as posters and brief recordings.
- Symposium was an international meeting, with more than 9 countries represented.
3:16 Overview of Scientists Present
- Broad group of individuals, including PhD scientists, bench scientists, clinicians who are looking at standards of care and how to improve care.
- Opportunity for learning between the groups is rare and valuable.
4:12 Symposium Highlights
- Molecular genetics and cells of PWS
- Insights from the animal models
- Clinical studies
- Genetic therapy
5:34 Why Is FPWR Supporting Gene Studies?
- We can be much more efficient and effective at developing therapies if we understand what is different in PWS compared to typical cells. What do the genes in the PWS region normally do? And how, when these genes are lost, do we get the symptoms associated with PWS?
- Understanding at the molecular and cellular levels helps identify targets for therapy.
- This work is important because it will allow us to develop therapies more effectively and more efficiently to reach the ultimate goal of identifying new targets for treatment.
6:56 PWS Region of Chromosome 15
- PWS region in chromosome 15: all of the genes shown in blue [on slide], are genes that are expressed only from the father’s chromosome.
- These are the genes that lose expression in PWS.
- Some of the things these genes do: make proteins, make RNAs, or regulate other RNAs.
- We have learned a lot about this region over the past 25 to 30 years since this region was really defined.
- MKRN3 gene is important in triggering puberty — that’s why we see incomplete sexual development in PWS.
- NDN gene has a role in helping neurons differentiate. When we lose that gene, there are some respiratory differences, which may underlie sleep disorders.
- MAGEL2 gene mutations cause Schaaf‑Yang Syndrome, which has a lot of commonalities with PWS.
- Losing MAGEL2 is likely a big contributor to the PWS phenotype or characteristics.
- We also know this RNA over here, SNORD116, is critical in PWS because every person who has the symptoms of PWS has lost SNORD116, and that's where it gets really complicated. RNA transcripts are processed into smaller transcripts and experimentally, it’s difficult to tease out which of these processed fragments is doing what in the cell.
9:58 Abstracts on Molecular Genetics/Cell Biology
- Potential Role of the N‑terminal domain of the Shaaf‑Yang syndrome protein MAGEL2 in RNA metabolism.
- Rachel Wevrick, PhD, University of Alberta, FPWR scientific advisory board.
- Dr. Wevrick is looking at the MAGEL2 protein and trying to characterize it better, figuring out what that structure is.
- Her lab is also looking at what proteins are associated with that part of MAGEL2, and they found that MAGEL2 may have a role in RNA metabolism.
- The Role of SNORD115 and SNORT 116 Clusters in the Development of Prader‑Willi Syndrome. Aleksandra Helwak, PhD, the University of Edinburgh.
- Non‑coding RNAs Associated with Prader‑Willi Syndrome Regulate Transcription of Neurodevelopmental Genes in Human Induced Pluripotent Stem Cells. Monika Sledziowska, PhD, The University of Birmingham.
11:38 Molecular Changes in Prader‑Willi Syndrome Neurons Reveals Clues about Increased Autism Susceptibility
- Caitlin Victor is one of the young investigators that we're really excited to see in the lab.
- Study uses baby teeth that have fallen out of the mouths of our kids.
- They're able to extract stem cells from those baby teeth and then grow them into neurons in a dish.
- A great source of neurons from someone with PWS without having to take neurons, for example, from their brain.
- Lab is always seeking donations of baby teeth.
- They presented about the gene expression changes that they see when they compare any PWS neuron to any typical neuron.
- Identified some cellular molecular changes in deletion versus UPD and then in UPD plus minus autism.
- They found the mitochondria seemed to be different in kids with autism versus kids with PWS but without autism.
- Following that up with some additional studies on the bio energetics of mitochondrial function in PWS neurons.
- These are genes that are important in making mitochondria and keeping them healthy.
- There are already some drugs that target these pathways, so the researchers will try out those drugs in the neurons from the baby teeth.
- They will also target PWS UPD‑specific changes by using molecular techniques to reduce the levels of UBE3A and then see how that impacts the cells.
- Hope that gives us ideas about new ways to target some of the specific challenges that we see in different subtypes of PWS.
15:38 Insights from Animal Models of PWS
- We have a lot of rodent models of PWS mice, and now a rat model of PWS.
- However, there are challenges. Mice don't fully recapitulate the characteristics. They don't typically get very overweight and don't have the same food drive that we see in humans.
- But nonetheless, there are a lot of features that they do have, and a lot of ways that those models can be used to better understand PWS.
- Comparison of Mouse Models Reveals a Molecular Distinction Between Psychotic Illness in PWS and Schizophrenia came from Anthony Isles, a fantastic animal model researcher in the UK (Cardiff University). He is a member of our preclinical animal network, and has a lot of expertise in PWS mouse models and PWS behaviors.
- Dr. Isles is specifically looking at the mouse models and their behaviors and seeing if he can gain some insights into the more serious mental health issues that some of our kids will have as they reach adulthood.
- Marrying the behavioral modeling in the mouse with some genetic data from humans that have mental illness to try to define those pathways that are present in PWS that make some with PWS more susceptible to serious mental health issues.
17:26 More Animal Model Insights
- Deficiency of the paternally inherited gene Magel2 alters the development of separation‑induced vocalization and material behavior in mice, Yale university.
- Gabriela Bosque‑Ortiz presented about the MAGEL2 mice and showed they actually use ultrasound to call their mothers to them when they're little babies, and the PWS mice don't do that. That causes a disruption of that maternal caring for the baby — a really new and interesting insight into social communication that may pave the way for interventions.
- Characterizing the energy balance phenotype of MAGEL2‑deficient rats.
- Elizabeth Mietlicki‑Baase, PhD, University of Buffalo, is looking at the new PWS rat model that FPWR funded.
19:35 Understanding Changes in Oxytocin in PWS
- We also heard from a pair of researchers who have collaborated quite a bit over the years, Dr. Francoise Muscatelli, PhD, who's an expert in PWS mouse models, and Dr. Sebastian Bouret, PhD, who is an expert in neurobiology.
- They are looking at the brains and neuronal development in those animals to understand the changes in oxytocin in PWS.
- The investigators have shown a deficiency of oxytocin neurons in both mice and humans with PWS, and in mice, if you give that oxytocin back shortly after birth, it improves social cognition and behaviors.
- They are also examining how oxytocin is needed and how it functions across the lifespan by essentially using a genetic toolbox to turn oxytocin neurons on and off in these mice and looking at how that impacts development and metabolism.
- They looked at how inactivation of oxytocin neurons at birth or in adolescence leads to autism‑like behavior.
- They've also shown that oxytocin is important and in a particular system that regulates metabolism in the hypothalamus.
- They've also shown that if you take juvenile mice and inhibit oxytocin at that point, it increases the fat mass and has effects on social interaction and cognition, as well as effects on metabolism and body fat.
- Work is ongoing and aimed at teasing out when oxytocin is going to be most useful for aspects of PWS.
22:23 Clinical Sessions
- Levo Therapeutics presented at the PWS Family Conference on Carbetocin to reduce hyperphagia and behavioral distress in PWS (results of the CARE‑PWS Phase 3 study).
- Another Phase 3 clinical trial looked at DCCR.
- Upcoming planned clinical trials include:
- Radius Health—a synthetic CBD oil oral solution.
- ConSyance Therapeutics —CSTI‑500 a novel triple reuptake inhibitor of dopamine, serotonin, and norepinephrine for managing PWS symptoms.
- UC‑Irvine studying oleoylethanolamide (an endocannabinoid‑like lipid) for hyperphagia.
23:24 Clinical: Developing Tools for Clinical Studies
- Several presentations were about hyperphagia.
- Early Hyperphagia in PWS Compared to Other Neurodevelopmental Disorders found that some kids with Angelman syndrome, which is also located in the PWS region, also seemed to have some hyperphagic behaviors.
- A Study from Trinity College, in Dublin, Ireland pilot tested a food‑related attentional (FAB) task in typically developing children.
24:59 What Schaaf‑Yang Syndrome Can Teach Us About PWS and Vice Versa
- Dr. Christian Schaaf, Heidelberg University, is the physician scientist who first described Schaaf‑Yang syndrome.
- He has been working on it since its description almost a decade ago, both on the clinical side and on the molecular biology side.
- One of the key components of his research is comparing how individuals with Schaaf‑Yang differ or are similar to individuals with PWS.
- Schaaf‑Yang syndrome was initially identified in just a handful of individuals, but that pool of patients has grown over the years.
- He described the cause of the syndrome: when the MAGEL2 gene is cut off, when it has a mutation that stops it, it results in Schaaf‑Yang syndrome.
- Dr. Schaaf has been looking at the overlaps between the phenotypes and has found a lot of similarities.
- When you mutate just L2, you get hypotonia at birth, feeding difficulty, sleep disruption, growth hormone deficiency, and other hormonal changes that are very similar to PWS.
- There are some unique things about Schaaf‑Yang compared to PWS:
- Individuals with Schaaf‑Yang often have contracture where their muscles tighten up and can’t easily open.
- They may have more severe intellectual disability and a higher rate of autism.
- Initially, there was not very much obesity and hyperphagia identified in people with Schaaf ‑Yang syndrome. But, in fact, as more patients have come to light and Dr. Schaaf has seen more older patients, he is changing his thinking on that; as kids get older, they do seem to have more food seeking.
- They do very easily gain weight, like our kids with PWS.
- There seems to be more and more overlap between PWS and SYS, indicating that MAGEL2 is particularly important in our PWS region.
28:00 MTOR Regulation in SYS and PWS
- Dr. Schaaf has looked at a particular pathway, the mTOR pathway, and seen that it is upregulated so it's high in SYS and PWS.
- mTOR is a protein that's a component of a key cellular pathway, important for nutrient sensing, regulating cell growth, and homeostasis.
- There are already drugs available that will modulate mTOR levels, and Dr. Schaaf is testing rapamycin in Magel2 deficient mice.
- He's already looked in some cell models and shown that it returns mTOR levels back to a kind of a normal level.
- Now, with FPWR funding he is testing that in mouse models and finding this pathway is important throughout the body, and particularly important in muscles.
- MAGEL2‑deficient mice are kind of couch potatoes; they don’t like to run, they like to sit around. They don’t like endurance exercise; they’re not marathoners.
- He is testing to see if bringing the mTOR levels down will help those aspects of metabolism and endurance in mouse models of PWS.
- This is exciting work because it does have the potential to translate fairly rapidly into the clinical situation.
- There is a lot of drug development. There are some drugs already, and then there's new drug development that impacts the pathway.
30:10 Social Skills Training Program in Young People with PWS
- Elisabeth Dykens, PhD, is a long‑term researcher in the PWS field.
- She has focused her career on helping families with neurodevelopmental disorders, including PWS, focusing on those quality of life issues.
- She has done a lot of work understanding the behavioral differences and social cognitive differences in PWS: why it's difficult for our kids to make friends and keep friends.
- Social isolation and loneliness are very common in PWS, along with behaviors like preservation and temper outbursts, and Dr. Dykens and her team are really interested in how we work with adults with PWS and help them develop better skills so that they can improve these aspects of their life.
- This was a zoom‑based intervention, even before the pandemic.
- They called the program Building Our Social Skills (BOSS), and it looked at recognizing emotions and some really practical, concrete skills and regulating emotions.
- They described the following outcomes of BOSS:
- Robust improvements in social cognition, awareness, social awareness.
- Participants and parents said they had more friends after the program.
- Participants described fewer feelings of loneliness.
- Clinicians saw improvements in social skills among participants.
- Dr. Strong’s son participated in the BOSS program.
- Next step is possible development of a more widespread curriculum to benefit people with PWS and other developmental disorders (Vanderbilt University).
33:27 Newborn Screening for Chromosome 15 Imprinting Disorders
- This clinical session developed by Dr. David Godler, PhD, at Murdoch Children’s Research Institute, Australia, is a newborn screen.
- With funding from FPWR and other entities, Dr. Godler has developed a test that can detect PR release syndrome, Angelman syndrome, and duplication 15 syndrome in one test in a blood spot.
- Why would we want to do newborn screening?
- Babies with PWS are not always identified at birth. Probably 20‑25% of kids with PWS still are not getting picked up in that newborn period; it’s really dependent on the physician who's in charge. If they're familiar with PWS, if they suspect PWS, then they'll order the right tests.
- Certain groups — rural areas, ethnic minorities— are being under-diagnosed.
- We have very good evidence that early intervention and growth hormone therapy improve outcomes for individuals with PWS.
- A molecular test to detect PWS with greater than 99% accuracy is available.
- The goal is to keep costs down by testing for 3 chromosome 15 disorders in one test.
- Dr. Godler screened about 16,000 blood spots in Australia and identified two babies with PWS, two with Angelman syndrome, and one baby with Dup15.
- Next steps: expand this pilot in other countries, including the US, and see if it's feasible to implement in the US.
37:07 Gene Activation as a Strategy for PWS Genetic Therapy
- In the normal situation, the PWS genes are only expressed from the chromosome that came from dad, but all of our kids with PWS, whether it's PWS by deletion, PWS by UPD, or by imprinting, they all have the genes sitting there on the mom's chromosome, but they're silent.
- A lot of the work is trying to activate those genes, asking whether they can be awakened and then asking the questions: Would it matter if they are? And at what point during life, would it have to be done in order to have a positive effect?
- Many questions are being investigated. When will gene activation need to occur to have an effect? What organs and cell types need to be targeted? What are the possible side effects? What are the genotype‑specific issues?
- Here is a list of some of the recent FPWR‑funded projects that are looking at these questions.
- Precise Epigenome Editing as a Novel Therapeutic Opportunity for Prader‑Willi Syndrome, Sibtain Haider, University Medical Center, Frieburg.
- Hypothalamic BDNF Gene Therapy Ameliorates Abnormal Metabolic Function in the Magel2‑null Mouse Model of Prader‑Willi Syndrome, Nicolas Queen, The Ohio State University.
- Dr. Marnie Blewitt is doing some really interesting work on this protein called SMCHD1.
- This protein is known to be one of the important proteins in keeping the mom's chromosome 15 silent.
- The concept is what if you edit out SMCHD1, could we reactivate those genes?
- One of Dr. Blewitt’s earlier studies showed that eliminating SCHMID1 allowed the PWS genes on the maternal chromosome to “turn on.”
- She's extending that work, looking at different approaches to see if inhibiting SMCHD1 would be a safe and effective approach, to activate expression of MAGEL2 and the other genes. When would that have to be done and what would be the impacts?
- Most of their work was in mouse models, but they are now looking at human cells to see if the results hold.
- SMCHD1 is an N enzyme, and enzymes are considered drug‑able targets. So she's doing a high screener to find drugs that will inhibit SMCHD1.
43:15 Concluding Remarks
- You can always contact anyone on our research team with specific questions, or if you have specific things that you'd like to hear about.
- Please contribute to the research. If you have a loved one with PWS, consider joining the global PWS Registry; that is such an important resource. We learn so much from everyone who is involved there.
- Consider signing up for the PWS clinical trials alert, even if you are not at a point where you want to enroll in a clinical trial.
- FPWR also will send out requests for baby teeth, poop, or other opportunities to contribute to clinical trials.
- Consider enrolling in clinical trials. There are other opportunities to be advancing PWS research.
- Thank you to all of our donors. So much of this research would not have been possible were it not for the support of our community and our donors.
45:23 Q & A
- BOSS curriculum can be taught by people who are not PWS experts.
- Many individual presentations will be available on the FPWR website/blog.
- CBD that is being studied is made in a lab and different from less‑regulated CBD from a grocery store or market.