Projects

The PRETEND program, developed by Dr. Dimitropoulos and her team, has been shown to improve aspects of social, emotional, and cognitive functioning in preschool and school age children with PWS. The purpose of this funded project is to make the PRETEND Program available to more families by establishing a platform to train interventionists to use...

Understanding the greatest clinical challenges is important in PWS, but there are individuals with PWS who are not participating in registry studies or surveys. Insurance claims data can be used to identify most people with PWS receiving care in the US. This project will analyze a vast database of claims from emergency departments and hospitals...

The SNORD genes are known to be very important in PWS, but there is a lack of appropriate tools to study the target and function of these genes. Dr. He and his team have developed two new methods that can map the targets of the SNORD genes. They will apply these new methods to mouse models and human cell lines with a deficiency in PWS-encoded...

Dr. Schaaf’s previous research showed that the ‘support cells’ in the brain (astrocytes) express receptors for oxytocin, are critically involved in the modulation of social behavior and anxiety, and that there are differences in both number and anatomical location of these astrocytes in healthy mice compared to a PWS mouse model. In this second...

Through previous work using a new optimized method, Dr. Whipple discovered that Snord116, a driver of PWS, directly interacts with ribosomes, the machinery that produces proteins in the cell in mouse neurons. In this funded project, they will apply their optimized method to human neurons to ask if the interaction between SNORD116 and ribosomes is...

Studies using cell and animal models are needed to better understand the normal function of MAGEL2 and how mutations or loss of the protein underlies both the PWS and SYS phenotypes. This funded project will support a postdoctoral fellow in Dr. Christian Schaaf’s lab to investigate the molecular biology of MAGEL2 in both PWS and SYS. This will...

Directly measured, objective outcomes are needed for Prader-Willi Syndrome (PWS) clinical trials for accurate assessment of treatment efficacy. We will conduct in person focus groups of primary caregivers of children between 8-17 years with PWS to review potential options for wearable devices and options for daily diaries/data entry, and use this...

In previous research, Dr. Hall has found that altered internal bodily cues (interoceptive processes), such as pain, itch, and sensual touch, may be involved in skin picking behavior in PWS. Here, he will employ a sophisticated brain imaging method called functional near-infrared spectroscopy (fNIRS), which allows brain activity to be measured...

This research will use state of the art neuroimaging techniques to advance our understanding of the neurobiology of two of the most challenging and difficult to manage aspects of PWS: hyperphagia and psychosis. The investigators will determine if imaging can detect changes in hypothalamic function in relation to eating behavior in PWS as well as...

Working with the Autism BrainNet, Dr. Yeo and his team will examine hypothalamic tissue samples from six individuals with PWS. The research team apply cutting edge molecular analysis to these precious samples and to map the architecture of the PWS hypothalamus, providing insight into the changes underlying appetite control. They will create a...

This project will explore how the gut microbiome influences metabolic health in PWS. Dr. Haqq is collaborating with one of the world’s leading metabolomics lab (Dr. David Wishart) to characterize ‘metabolite’ profiles in children and adolescents with PWS and explore the links between blood metabolites, the gut microbe, and metabolic health in...

The probiotic supplement, BPL1, shows promise improving metabolism and behavior in people with PWS, but more work is needed to understand how this gut microbiome intervention can be optimized. This project aims to understand how probiotic supplementation improves metabolic and mental health in individuals with PWS by influencing brain circuits...

These researchers hypothesize that PWS is associated with changes in the perception of food odors, which may drive some aspects of hyperphagia. In this study, Drs. Steculorum and Tauber will examine the role of olfaction in both patients with PWS and a mouse model of PWS, and will explore how one potential treatment, oxytocin, impacts the...

People with PWS have abnormally high amounts of REM sleep and inappropriate occurrence of REM sleep in the middle of active wake periods. A specific population of neurons in the lateral hypothalamus secretes a neuroactive substance called melanin-concentrating hormone (MCH), which control REM sleep. To determine if MCH neurons are overactive in...

The purpose of this project is to develop a cellular assay specific to circadian rhythm defects identified by the Reiter laboratory. The eventual goal is to use this assay to screen for compounds that can normalize these circadian defects, potentially identifying drugs that would address developmental and metabolic changes that accompany...

FPWR has established the Pre-clinical Animal Network (FPWR-PCAN) initiative to rigorously define the characteristics (phenotype) of PWS mouse models compared to ‘wild type’ or typical mice. This project will transform this effort into a valuable translational platform for the PWS scientific community by conducting multi-step, comprehensive...

Inhibiting SMCHD1 is a potential new treatment for PWS and SYS. In the first year of this study Dr. Blewitt provided evidence that SMCHD1 acts in a similar way in human cells and quantitated the level of gene activation that occurs in a mouse model when SMCHD1 is removed. In this second year of funding, Dr. Blewitt will attempt to determine what...

The goal of this study is to further evaluate whether the hormone, CART, is a viable therapeutic target for the treatment of the insatiable appetite associated with Prader Willi Syndrome (PWS). In this application, we propose to continue our studies through the following Aims: 1. determine if injection of CART can decrease appetite in obese...

Recently, Dr. Cao validated the safety and efficacy of a novel brain-directed gene therapy (BDNF) for metabolic and behavioral deficits observed in a preclinical mouse model of PWS, and identified BDNF as a potential therapeutic target to treat metabolic and behavioral aspects of PWS. Follow-up studies by our group investigated the genetic...

Dr. Mitchell and her team have been investigating how beloranib, a drug that effectively reduced hyperphagia and induced weight loss in individuals with PWS, worked. By defining downstream effectors of beloranib’s hyperphagia-reducing action, they hope to identify a safe and effective drug to treat hyperphagia in PWS. Dr. Theresa Strong, Director...

Drs. Urban and Parker will examine genomic data from marmosets to lay the groundwork for the potential development of a novel animal model of PWS. The feasibility of generating a genetically engineered marmoset model for PWS will be evaluated and a detailed plan for generating this model will be generated.

Dr. Fon Tacer’s studies will provide mechanistic insights into how loss of the PWS-region gene, MAGEL2, results in deficits of secretory granules (SG), which are essential for the proper release of hormones from cells. Such an understanding is critical for determining how to restore neuroendocrine function for therapeutic purposes. This project...

Our recent research identified a new brain pathway, the cerebellum-ventral striatum circuit, in regulating appetite and satiation. In the proposed study, we plan to test whether safe, non-invasive modulation of this circuit, using a technique called transcranial magnetic stimulation (TMS), can impact the function of this circuit and reduce food...

This research team is exploring a novel approach to activate maternal gene expression from the PWS region of chromosome 15, using a small piece of RNA (short hairpin RNA) to interfere with a protein that silences the maternal chromosome.

These researchers have demonstrated that activation of a distinct class of cerebellar neurons dramatically decreases food intake by reducing meal size without compensatory changes to metabolic rate. In this proposal, we will characterize this novel cerebellar satiation network and evaluate whether this network is disrupted in PWS mouse models and...

This project aims to evaluate a parent training program (PWS Smart Start) for helping caregivers develop the skills they need to address challenging behavior and skill deficits common among children with Prader-Willi Syndrome. This project begins to lay the foundation for behavior analytic services for children with PWS, with the end goal of...

Currently, hyperphagia is often assessed by proxy informants on the Hyperphagia Questionnaires. Leveraging insights from previous research -- and with input from a PWS Advisory Board, PWS focus groups and our own experience in developing other PWS-specific measures—this project will develop a self-report measure of hyperphagic symptoms for...

This proposal investigates the development of a potential epigenetic therapy for PWS. Year 1 of this project showed the researchers were able to reactivate several maternal silenced PWS genes. In year 2, they will determine the epigenetic requirements for a uniform and stable reactivation of the maternal PWS region in human cells using transient...

In year 1 of this project we found increased UBE3A levels in white blood cells was linked to more severe autism features, but only in non-deletion PWS (most matUPD). In year 2, we will analyze the dataset created in year 1 to help us understand how activity of UBE3A and other key genes (related to inflammatory and other dysregulated pathways)...

In this project we propose to use a newly-developed powerful tool to identify the specific nerve cells and genes that cause the hyperphagia in individuals with PWS and then screen for drugs to correct their functions and treat the obesity associated with PWS using the MAGEL2-null mouse model. We hypothesize that those cells showing significant...

One effect of the lack of Magel2 in PWS is lower production of a brain neurotransmitter called orexin. Orexin is key to regulating a number of physiological processes, including hunger and physical activity, and we hypothesize that the obesity and related metabolic function symptoms seen in PWS is linked to a reduction in the levels of orexin in...

Our project aims to test the hypothesis that alterations in certain specific lipid sensors and mediators in the hypothalamus may contribute to the disrupted feeding behavior and the altered metabolic phenotype associated with PWS at different stages of postnatal development. These studies will try to reverse the metabolic alterations observed...

In this project we propose to use a newly-developed powerful tool to identify the specific nerve cells and genes that cause the hyperphagia in individuals with PWS and then screen for drugs to correct their functions and treat the obesity associated with PWS using the MAGEL2-null mouse model. We hypothesize that those cells showing significant...

We expect that discovering the direct functions of snoRNAs will uncover new mechanisms – as well as revealing the fundamental basis of PWS. We propose to create a wide picture of RNA-RNA and RNA-protein interactions during the development of brain cells, focusing on interactions of SNORD116, as well as SNORD115 and other ncRNAs synthesized from...

Data from the first year of this project that in the postnatal period mice that lack Snord116 (Snord116del) have dramatic changes in neuronal morphology in both the cortex and hippocampus, brain regions that are essential for cognitive function. In the second phase of this project, we will characterize the electrical activity and functional...

With previous FPWR funding, Dr. Yu used advanced, single-cell sequencing to characterize changes in hypothalamic cells in a PWS mouse model and identified activation of a gene important in stress response and energy metabolism, Fkbp5. Here she will test whether inhibiting Fkbp5 rescues deficits in a PWS mouse model.

Dr. Ross will investigate how feeding behavior and cognitive flexibility are jointly regulated in the prefrontal cortex of the brain, in neurons expressing MC4R. This study may define a neuronal circuit to target therapeutically.

Dr. Sweeney has shown that the melanocortin 3 receptor (MC3R) is important in regulating food intake and has developed an antagonist of MC3R that inhibits feeding. Here he will test whether inhibition of MC3R decreases food intake in a mouse model of PWS.

Dr. Blewitt has shown that inhibiting SMCHD1 allows several important protein-coding genes in the PWS to be expressed, but the effect is incomplete. Here she will determine the chromosomal landscape in the PWS region on the maternal chromosome and evaluate how that landscape changes when SMCHD1 is missing, paving the way for more efficient...

Dr. Fon Tacer has been investigating the function of the MAGEL2 protein and believes it plays an important role in how cells adapt to stress. In this study she will explore how cellular stress responses are altered when MAGEL2 is lost.

The Snord116 gene is critical in PWS, but its normal function is incompletely understood. Dr. Good will establish an atlas of where and when the SNORD116 RNA is expressed in the developing mouse brain and how it interacts with one of its putative target genes, Nhlh2, to gain insight into the underlying molecular basis of PWS.

Dr. Derek Tai developed PWS cell lines representing type 1 and 2 deletions and has grown them as 3-D brain organoids, recapitulating the hypothalamus, in a dish. He has applied cutting edge technology to understand how PWS neurons differ from typical neurons and has generated data on gene expression changes. In year 2, he will expand the study to...

Dr. Puleo and his team are investigating the use of peripheral ultrasound to modulate targets in the brain and impact energy balance and weight. They have strong preliminary data in several mouse/rat models of obesity and have performed early-stage clinical trials in healthy obese people. Here they will investigate mouse models of PWS to as a...

Dr. Singh and his team will be performing a clinical trial of bright light therapy in children (6-18 years old) with daytime sleepiness, and evaluating the effects on sleepiness, behavior and activity.

Differences in PWS symptoms across individuals may be due to variation in genes outside of the PWS critical region. To understand how genetic variants contribute to the severity and complexity of the disease, Dr. Bochukova will analyze variations in the genetic makeup of 160 PWS participants. With support from Soleno Therapeutics, biochemical,...

Dr. Kelleher and her group have been developing telehealth-based interventions to improve the mental wellness of those caring for individuals with neurodevelopmental disorders. Here, they will expand an existing caregiver support program (Well-CAST) to families with PWS and another disorder (Williams Syndrome, WS). They will evaluate different...

This study builds on the previous work of Dr. Godler, who developed a high throughput, economical test to detect chromosome 15 disorders in blood spots from newborns. Dr. Wheeler will transfer the technology to a newborn screening program in North Carolina to assess the feasibility of incorporating detection of chromosome 15 disorder into a...

Currently, there are no objective biomarkers of hunger/satiety for PWS, which can be a barrier in PWS research. This study aims to develop an objective biomarker for altered satiety and hyperphagia in PWS using an eye-tracking method (measuring where a person is looking) to measure attentional bias (AB; increased attention) to food. Previously,...

PWS is not the result of a single gene mutation but rather is caused by the loss of several contiguous genes, some of which interact with each other. In this project, Drs. Bouret and Muscatelli will study a new mouse model that lacks two PWS genes, Magel2 and Necdin. The goal is to understand how Magel2 and Necdin act together to influence brain...

In this project, Dr. Nicholls will begin studies towards an innovative gene therapy strategy for PWS, by developing a single adeno-associated virus (AAV)-vector that incorporates up to 80% of the PWS genes. This project will generate miniaturized components from the PWS genes and build an AAV vector carrying eight PWS genes. Delivery and...

In this project Dr. Lodato will use stem cells from PWS patients to generate human 3D cortical organoids (a ‘minibrain in a dish’). Human cortical organoids are valuable models that mimic aspects of human brain development, and analysis of these organoids is expected to shed light on how brain development in PWS differs from that in typical...

Dr. Reiter’s previous studies suggest that PWS neurons exhibit delayed maturation compared to neurons from typical individuals. Here, his team will use RNA sequencing during neuronal differentiation to better understand the molecular basis of the developmental delay and identify new targets for therapeutic interventions. His team will also...

Prader-Willi (PWS) and Schaaf-Yang syndromes (SYS) are disorders that are both caused by alterations of the MAGEL2 gene, which is either completely missing (PWS) or non-functional (SYS). Working with PWS and SYS mouse models, Dr. Schaaf will investigate the function of a brain ‘support cell’ (astrocytes), which have recently been found to be...

Preliminary research done by Dr. Grzechnik has shown that “long non-coding RNAs”, (lncRNAs) from PWS-region genes may act as important regulators in neurodevelopment. In this project, Dr. Grzechnik will study the changes that occur when the PWS lncRNAs are depleted during the early, middle and late stages of neuronal development.

Dr. Cao has been developing a gene therapy approach that addresses the major symptoms of PWS, through the delivery of a gene that modulates metabolism and behavior (Brain-derived neurotrophic factor, or BDNF). In her 2nd year of funding, her team will assess whether this single-dose viral gene therapy into brain improves metabolism and behavior...

Hyperphagia is thought to be a problem of neurons in the hypothalamus, caused by a dysregulation of neurons that signal being full and being hungry. Disruptions in the code for chemical modifications of RNA (called the epitranscriptome) can have detrimental effects on how neurons function. This project will use human hypothalamic hunger neurons...

A protein called CART controls appetite and body weight in both lean and obese rodents and mutations in the CART gene have been linked to obesity in humans. The protein GPR160 helps CART signal brain cells to control appetite. However, CART and GPR160 have not been studied in PWS before. Therefore, this project will evaluate the role of CART in...

Pancreatic beta cells produce and secrete two hormones, insulin and amylin, that are important regulators of food intake. These beta cells also express several PWS-region genes, but their function in the pancreas isn’t known. This project will shed light on the role of PWS genes in pancreatic beta cells by studying how PWS genes are regulated in...

Two genes disrupted in PWS are SNRPN and MAGEL2, the latter which is the causal gene for Schaaf-Yang syndrome (SYS). The goal of this study is to identify and compare behavioral characteristics and protein profiles of rat models that are deficient for Snrpn and Magel2. These studies will not only provide us a deeper understanding of...

Dr. van Bosse and his team will define the typical posture of grown children and adults with PWS without spinal deformities (e.g., scoliosis). These results will be compared to results from the general population will be used to create guidelines for the alignment of the spine after spinal surgery in children with PWS.

Dr. Mietlicki-Baase and her team will investigate neural/neurohormonal control of energy balance in a rat model that lacks Magel2, a gene that is lost or mutated in Prader-Willi syndrome (PWS) and Schaaf-Yang syndrome (SYS). They will test feeding motivation behaviors and examine the brain areas that control energy balance. They will also...

Dr. Jo and his team are working on appetite-controlling pathways in the brain. Research has shown that mice lacking the Magel2 gene have fewer and less functional proopiomelanocortin (POMC) neurons, which are important in regulating appetite. These neurons appear to work through the amygdala, which is a part of the brain that is important in...

The cognitive challenges experienced by many individuals with PWS remains poorly understood. Pilot data obtained in the Wells laboratory indicates that loss of expression of PWS-region gene, Snord116, leads to reduced length and branching of a certain type of neuron in the cortex of the brain. In this project they will use specialized techniques...

Guanfacine XR (brand name Intuniv) is a medication for ADHD that improves impulse control. Dr. Singh has noted improvements in aggression and self-injury in PWS patients in his practice when using this medication. Here, he will perform a controlled clinical trial to evaluate the efficacy of guanfacine for treating these aspects of PWS, and also...

Dr. Tai and his team have used CRISPR genome editing techniques to generate a series of PWS deletion stem cells (small deletion, large deletion and single genes). Here, they will drive the cells to become hypothalamic neurons in a lab dish, then apply advanced technologies to study the cellular properties of these PWS neurons compared to typical...

Dr. Bang and her team will apply a series of ‘assays’ (lab tests evaluating cell function) to PWS patient-specific stem cells (iPSC) that have been driven to become cortical neurons in a lab dish. Once validated, these assays can be used to discover novel therapeutic targets for PWS, screen for drugs that can correct impaired neuronal function,...

Dr. Resnick and his team have developed a mouse model of PWS that allows precise activation/replacement of the missing PWS genes at different times during development and in different tissues. In this second year of funding, they will work to reestablish gene expression and determine the effects on the potential reversal of traits. This study...

Dr. Isles and other researchers have shown that abnormal placental function can have profound consequences for brain and behavioral development in the offspring, and that abnormal signaling from the fetal placenta can also have consequences for maternal brain and behavior, which in turn may impact offspring neurodevelopment. This project examines...

Hyperphagia and the associated metabolic dysregulation is one of the greatest challenges that individuals with PWS and their families face on a daily basis. Dr. Cao has developed a gene therapy that targets the metabolic roots of PWS within the brain’s center for energy regulation. Their group has developed an approach using a single dose of a...

Dr. Mussolino and his team will use a novel approach to activate the maternal genes in the PWS regions. They are developing ‘designer epigenome modifiers’ (A-DEMs), to target key elements of the PWS-critical region on chromosome 15. This approach may allow more specific activation of genes in the PWS region of chromosome 15 for genetic therapy...

The goal of the second year of this research project is to determine, using a preclinical mouse model of PWS, when do the maximal health and biological effects of oxytocin occur (birth, infancy, puberty, or adult life). The study also examines neurological mechanisms by which oxytocin treatment exerts its effects on feeding and behavior in PWS....

Dr. Reiter’s lab looks at stem cell lines from the teeth of PWS subjects to look at the sleep/wake cycle, called the circadian rhythm. People with PWS have a hard time with regulating this cycle. This project will use these stem cell lines to look at the PWS circadian rhythm patterns, as well as changes in DNA that are known to happen at...

Dr. Dietrich’s lab has been working on “hunger” neurons, Agrp neurons, that are contained in the hypothalamus in animal brains. They have found that PWS-related genes, particularly Magel2, are enriched in Agrp neurons. In the second year of funding for this study, they will use a mouse model that is missing Magel2 to look at the function of the...

Dr. Grzechnik’s lab is interested in uncovering the biological mechanisms underlying PWS. The deletion in the PWS locus affects the regulation of gene expression in neurons, but scientists are not exactly sure how this mechanism works. This current project is testing how coding and non-coding regions of the human genome are transcribed in cells...

Dr. Iglesias has been working on potential genetic therapies for Prader-Willi syndrome and has shown that ‘epigenome editing’ can reactivate the maternal genes in the PWS region in human cells. The current study will focus on determining the molecular requirements to permanently reactivate the maternal genes in the PWS region, so that gene...

Dr. Godler’s lab is interested in identifying early predictors of autism and serious mental illness in PWS. In their preliminary data, they have found that inflammatory pathways linked to UBE3A (a key gene that regulates normal brain development and immune cell function) were affected differently in PWS caused by uniparental disomy (UPD),...

In a summer project, a student in Dr. Wells’ laboratory will explore the basis of impaired cognitive ability in a mouse model of PWS. The developmental differences in neurons, specifically examining the dendrites, which are the branches of the nerve cell. Size, shape, and branching of the neurons in PWS mice will be characterized and compared to...

Dr. Koren studies how DNA is copied (replicates) as cells grow and divide. He previously discovered that the PWS region of chromosome 15 is unique in that the timing of DNA replication on the father’s chromosome is very different than the replication of DNA on the maternal chromosome 15. He hypothesizes that loss of the PWS genes on the father’s...

This funded project, led by Dr. Cai, will look at the problems in satiety (the feeling of being full) signaling in a mouse model of PWS. Dr. Cai thinks that a specific set of neurons in the amygdala region of the brain do not receive or respond to satiety signals properly, and that is why the appetite suppression in PWS is impaired. He will use...

Dr. Atasoy and his team have recently discovered that the protein Magel2 is important in allowing oxytocin neurons in the brain to communicate normally. These neurons are involved in social behavior, cognition and infant feeding. This funded project will study a mouse model of PWS that is lacking Magel2, to understand how loss of Magel2 impacts...

Dr. Holland is a psychiatrist with a long-standing interest in understanding why individuals with PWS are susceptible to mental illness. In this funded project, he will use a brain imaging technique called “magnetic resonance spectroscopy” to look at levels of the neurotransmitter, GABA, in the brain. Dr. Holland thinks that differences in GABA...

Dr. Schaaf and his team have examined a mouse model of Prader-Willi syndrome (PWS) and Schaaf-Yang syndrome (SYS), as well as neurons made from skin cells of people with SYS, and have found a significant overactivation of an important cellular pathway called the “mTOR” pathway. There are currently FDA-approved drugs that can reduce the activity...

Dr. Potts and his team have studied cells from PWS ‘baby teeth’ to identify changes in cellular function in PWS. They found that the vesicle recycling is altered in PWS cells, and that this is a consequence of loss of the gene, MAGEL2. They also described that developmental changes in cells from children with PWS compared to typical children. In...

Dr. Malcolm Low is an expert in the biology of the nervous system as it relates to appetite. Previously, he has discovered that the Magel2 protein is active in a set of neurons in the brain that regulate appetite. In this project, his team will apply a cutting edge technology, “single cell sequencing”, to determine how these neurons and brain...

In Prader-Willi and Schaaf-Yang syndromes, the MAGEL2 gene is lost or mutated. It is important to understand the normal function of the MAGEL2 gene to better understand what happens when that function is missing. Dr. Rachel Wevrick and her team, in their first year of funding, discovered that MAGEL2 normally works with other proteins that help...

Understanding temper outbursts are a significant challenge in PWS, and little is known about why they happen so frequently. The investigators will use brain imaging to better understand GABA receptor activation across brain regions in times of frustration for those with PWS. Research Outcomes: Publications The characteristics of temper outbursts...