Funded Projects

Disrupting recruitment of a central epigenetic repressor in PWS

The protein G9a participates in silencing maternal copies of PWS genes. With expertise in G9a targeting, Dr. Al-Sady aims to define and specifically block the mechanisms bringing G9a to PWS genes without off-target effects. Dr. Theresa Strong gives a brief summary of this project during our Spring 2...

Identifying impaired neural pathways of satiation for Prader-Willi syndrome

Dr. Cai previously discovered that the “fullness” signal hormone CCK is present at normal levels in PWS but apparently ignored, and even adding more is ineffective. To understand why, he will proceed with advanced brain imaging techniques to identify which cells in which brain locations are affected...

Precision neurotrophin intranasal delivery: BDNF meets extracellular vesicles for Prader-Willi syndrome treatment

BDNF has been remarkably effective in proof-of-concept studies but there has been no viable approach for delivery. This project, led by Dr. Simona Capsoni, will attempt to both develop and validate a novel, non-invasive, intranasal delivery strategy for BDNF in PWS. Dr. Theresa Strong gives a brief ...

Epigenetic activation of the PWS locus in post-mitotic neurons

Dr. Gersbach’s earlier success in unsilencing maternal copies of PWS genes in developing neurons will now be adapted to work in mature neurons. He will identify regulatory features hindering unsilencing in mature neurons and test combination therapies to enable stable reactivation in PWS patients of...

Allele-specific MAGEL2 mouse models to define circadian and sleep mechanisms in PWS and SYS syndromes

Sleep is a significant challenge in both SYS and PWS. This project, led by Dr. Andrew Liu, will use a new mouse model of Schaaf-Yang syndrome (SYS) to investigate how the protein MAGEL2 regulates normal sleep and other cyclic behaviors. Dr. Theresa Strong gives a brief summary of this project during...

Adapting a group intervention for emotion dysregulation in Prader-Willi syndrome

Dr. McKinney will assemble PWS families and medical professionals to adapt a group therapy where teens and their caregivers together learn skills to manage stress, emotions, and behaviors unique for PWS families with teenagers. Dr. Theresa Strong gives a brief summary of this project during our Spri...

ER chaperones and perinatal growth in Prader-Willi syndrome: therapy and mechanisms

With a newly established mouse model of PWS that remarkably models the unique pattern of nutritional phases in PWS development, Dr. Nicholls will measure gene expression, hormones, and metabolites to understand these phases, the triggers for transitions between them, and the ideal time for a treatme...

North American Clinical Care Consensus for Neonates and Infants (0-12 Months) with Prader-Willi Syndrome: Delphi Consensus Proposal

Drs. Roy and Bird will convene a panel of experts to develop guidelines for clinical care of neonates and infants with PWS.

Non-invasive stimulation of BDNF production in the hypothalamus to regulate satiety signalling

Lower levels of a specific growth factor (brain derived neurotrophic factor, BDNF) have been reported in people with PWS. Because BDNF is important in brain development and function, as well as appetite regulation Dr. Whitcomb’s group will test whether using an ultrasound technique in rodents can en...

An Artificial Intelligence Program to Determine the Nutritional Phase of PWS

Individuals with Prader-Willi syndrome (PWS) go through 6 nutritional phases (NPs), but investigators need a standard method of determining the correct NP. Dr. Driscoll has developed an NP questionnaire and an Artificial Intelligence (AI) model to accurately classify the NP in people with PWS, which...

Mapping the Genetic and Regulatory Architecture of the 15q11-q13 Region to Identify Neurodevelopmental Mechanisms for Prader-Willi Syndrome

The two main goals of this project are to use advanced genetic analysis to identify specific genetic variants within the PWS region that impact brain structure in typically developing children, and to investigate how the 3D structure of DNA within the PWS region affects the activity of these genes d...

Investigating the effect of targeting SMCHD1 in a whole locus disruption model of PWS

Dr. Blewitt has been working on a gene therapy approach for PWS that targets a factor called SMCHD1, which normally switches off the PWS genes. Here, her group will test whether removing SMCHD1 allows the PWS-regions genes to be expressed and improve symptoms in a PWS mouse model with an imprinting ...

Cholinergic Control in Prader-Willi Syndrome - Exploring a new route for therapy

Based on previous research, Dr. Azevedo believes that disrupted acetylcholine (ACh) signaling in the brain may be a key factor contributing to the symptoms of PWS. In this project, she will study how the loss of the PWS-associated gene, MAGEL2, affects ACh activity in a certain part of the brain (la...

Analysis of mitochondrial defects in PWS-UPD individuals with autism

Children with PWS also have a higher-than average incidence of autism, especially those with PWS due to uniparental disomy (UPD). Dr. Reiter’s group has shown that cells from individuals with PWS-UPD plus autism also have changes in their mitochondria. Here, they will use new tools to assess mitocho...

Spatial transcriptomics of the minimal critical region of the PWS locus in the human hypothalamus and cerebellum

Dr. Doege’s group will use novel, cutting-edge technology to examine how the PWS-region genes are expressed in the human brain, focusing on the regions that are critical for controlling feeding related behaviors. This approach will provide a high resolution understanding of where the PWS critical ge...

Neurovascular Plasticity as a Molecular Driver of PWS

This proposal aims to demonstrate that structural changes in brain capillaries are central to the metabolic and neurophysiological issues seen in Prader-Willi Syndrome (PWS). Dr. Schneeberger Pane believes the brain's local environment drives capillary changes, impacting brain plasticity and further...

Assessing DGKk dysregulation in Prader-Willi syndrome

Dr. Moine aims to elucidate the role of DGKk in PWS pathology and explore its potential as a biomarker and therapeutic target. Recent evidence suggests that SNORD116 may regulate the expression of DGKk, an enzyme crucial for lipid signaling pathways in neurons. DGKk controls the balance between diac...

Transcriptome-wide identification and functional annotation of PWS-encoded SNORD targets (Year 2)

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...

Investigating the role of Snord116 in ribosome biology (Year 2

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 t...

Deciphering the molecular mechanisms of neuronal development deficits in Prader-Willi syndrome: insights into hypothalamic dysfunction

By creating three-dimensional hypothalamic organoids from hiPSCs with PWS-relevant deletions, Dr. Tai will investigate how specific genetic changes drive molecular and cellular alterations in PWS. The study will identify disease-relevant genes, pathways, and cell types, establishing a framework for ...

MCH neuron dysregulation in the pathophysiology of Prader-Willi Syndrome (Year 2)

People with PWS experience abnormally high amounts of REM sleep and an inappropriate occurrence of REM sleep in the middle of active wake periods. Previous research has shown that neurons secreting a certain hormone (MCH) control REM sleep. To determine if MCH neurons are overactive in PWS, this res...

Investigation of Magel2 expression patterns in a novel rat model for Schaaf-Yang syndrome

Our understanding of cellular MAGEL2 functions in brain development and SYS pathophysiology is limited due to insufficient data on cell type-specific and development- dependent MAGEL2 expression patterns. Dr. Althammer's project will provide unprecedented information about RNA expression patterns in...

Defining isoform diversity consistent between the brain and blood, related to the severity of Prader-Willi Syndrome.

Dr. Godler has found one ribosomal gene called RPS18 to be upregulated in all types of cells in specific regions of the brain from donors with PWS. He then showed that this upregulation in blood was associated with severity of PWS in another group of living individuals, including intellectual functi...

Unraveling the mechanisms of cholinergic neuronal impairment in individuals with Prader-Willi Syndrome

This project aims to clarify the role of the brain’s cholinergic system in PWS and its connection to cognitive difficulties and hyperphagia. Dr. Yi and her team hypothesize that acetylecholine (ACh) deficiency in the brains of individuals with PWS may contribute to their cognitive impairments and ap...

Big Data for Prader-Willi Syndrome

Do GLP-1s work for PWS? Drs. Rubenstein and Stokes are surveying health records from 14,000 individuals living with PWS from 2014-2025 to identify which GLP-1s have been prescribed, how well they worked, and if there were any side-effects.

Cross-cultural Adaptation and Validation of the Food Attentional Bias Task (FAB-TASK) as a Potential Biomarker for PWS (Year 2)

Dr. Gallagher and team have been testing whether ‘eye tracking’ can be used as an unbiased way to assess food interest/hyperphagia in PWS. Initial studies were promising, and here they will test the reproducibility of their initial studies, which were done in Ireland, and see if the results hold in ...

Disentangling developmental and hormone responsive dysfunction of human hypothalamic circuits in Prader-Willi Syndrome

The focus of our proposal is to unravel the complexities of developmental and hormone-responsive dysfunction within human hypothalamic circuits in Prader-Willi Syndrome using cutting edge human brain circuits within a petri dish using organoids.

In vivo implementation of hypothalamus-specific exosomes to reverse the impact of Snord116 deletion

Dr. Lee and colleagues have been investigating the use of exosomes (small vesicles released from cells) to carry PWS genes to the hypothalamus in PWS mouse models, as a first step to gene therapy for PWS. Here they will use their engineered exosomes to test whether delivery of the PWS genes can reve...

Analysis of Delayed Neural Development in PWS DPSC Neurons (Year 2)

Dr. Reiter has used stem cells derived from baby teeth to look at differences in how PWS neurons in a dish develop compared to typical neurons. He has found changes in circadian rhythm and timing of development. Year 2 work will focus on ‘rescuing’ these characteristics by delivering different PWS-r...

Epigenome Editing for Stable Reactivation of Maternal PWS Genes

Dr. Gersbach continues his work examining advanced CRISPR tools to understand the regulation of gene activity in the PWS region and optimize gene activation strategies. Dr. Theresa Strong, Director of Research Programs, shares details on this project in this short video clip.

Revealing the Molecular Architecture of PWS Through Large Language Models for Targeted Drug Repurposing

Dr. Singh will apply artificial intelligence to PWS datasets to glean new information about pathways disrupted in PWS and possible targets for therapy. Dr. Theresa Strong, Director of Research Programs, shares details on this project in this short video clip.

Genetic Determinants Of Behavioral Physical And Physiological Characteristics of PWS (Year 2)

This second year of funding expands Dr. Bochukova's work to understand how genetic variants outside the PWS region influence the frequency and severity of symptoms associated with PWS. Dr. Theresa Strong, Director of Research Programs, shares details on this project in this short video clip.

Novel functions and translation mechanisms involving SNURF and neural-specific SmN spliceosomal protein

One of the major genes in the PWS critical region, SNURF-SNRPN, is relatively understudied. Here, Dr. McManus will use cell models of human brain, pancreas and heart to understand the function of the proteins that this gene produces. Dr. Theresa Strong, Director of Research Programs, shares details ...

The role of lateral septum neurons in the pathogenesis of Prader-Willi Syndrome

Dr. Azevedo is interested in a particular set of neurons (the lateral septum, LS, neurons) in the brain that express the PWS-region gene, MAGEL2, since these neurons may be important in controlling feeding behavior. Here, she will investigate whether LS neurons behave differently in PWS mice compare...

Molecular Underpinnings of Prader-Willi Syndrome

Dr. Carmichael has been investigating the changes in gene expression of PWS cells lacking SNORD116 genes compared to typical cells and has identified a set of 40 genes that are differentially expressed. In year 2 they will further characterize these genes and their role in PWS and will examine how S...

Non-coding RNAs in neuronal differentiation and PWS (Year 2)

Dr. Tollervey is an expert in snoRNA biology. He has been investigating the snoRNAs in the PWS region and has found that loss of the SNORD116 genes alters neuronal maturation in PWS cells. In year 2 of his funded project, they will use specialized techniques to identify the RNAs and proteins that in...

Spatial Molecular Imaging of the Human PWS Hypothalamus

Dr. Yosten is using a combined spatial imaging approach to perform a detailed analysis of the proteins and genes found in hypothalamus of individuals with PWS, in comparison to typical individuals. They will build a data-sharing platform that can be used by the entire scientific community to analyze...

Prefrontal cortex glutamatergic neurons as a target for metabolic and cognitive symptoms in a mouse model of PWS (Year 2)

Dr. Ross has been investigating a particular region of the brain (medial prefrontal cortex) and class of neurons in PWS mice, to understand their link to cognitive and metabolic changes in PWS. They will determine whether stimulating these neural circuits in the brains of PWS mice reduces food intak...

Obsessive-compulsive and psychotic-like behaviors across PWS subtypes: Developmental considerations

Dr. Evans has previously developed a well-validated measure of rigidity and obsessive-compulsive behaviors, as well as behaviors associated with psychosis. Here, he will work with the Global PWS Registry team to recruit families to complete these assessments three times over a year and see if they a...

Defining isoform diversity conserved in the brain and blood, related to the severity of Prader-Willi syndrome

Dr. Godler has been investigating cell-specific changes in gene expression in blood and brain tissue samples from individuals with PWS, with the goal of developing blood-based biomarkers of PWS severity. Here his collaborative will apply newer technologies to look at genes and proteins that are diff...

Using designer milk exosomes for restoring MAGEL2 expression in the brains of Magel2 knockout mice

Exosomes are nonviral fragments of cells that can be used for the delivery of genes. Dr. Zempleni has developed targeted milk exosomes and will apply that approach to deliver a critical gene from the PWS region, Magel2, to a mouse model of PWS. Dr. Theresa Strong, Director of Research Programs, shar...

An innovative non-viral delivery of CRISPR/dCas9 epigenome editing-based therapy for Prader-Willi Syndrome

Dr. Lu will use an innovative delivery system to achieve CRISPR gene activation in a new mouse model of PWS. Dr. Theresa Strong, Director of Research Programs, shares details on this project in this short video clip.

Cellular and molecular basis for obesity in PWS (Year 2)

This second year of funding builds on excellent work to date from the Friedman lab, which has identified a new subset of neurons in the hypothalamus and a novel gene that may be driving hyperphagia in PWS. They will explore how Magel2 impacts the function in these neurons and whether a pharmacologic...

Endoplasmic reticulum (ER) chaperones in Prader-Willi syndrome: Therapy and mechanisms

Dr. Nicholls has identified deficits in a set of proteins that facilitate the folding and maturation of other proteins, ER chaperone proteins. He believes deficits of these proteins in the pancreas is an important contributor to endocrine dysfunction in PWS. Here he will assess the ability of drugs ...

Similar metabolic pathways are affected in both Prader-Willi Syndrome and Congenital Myasthenic Syndrome-22

Dr. Creemers has found that PWS has molecular similarities to another genetic disorder called CMS22. Individuals with CMS22 deficiency also have hypotonia and poor growth, followed by the development of hyperphagia. Here the lab will evaluate if the protein associated with CMS22 (PREPL) can rescue t...

Elucidating Phenotypic Differences between PWS and SYS: Exploring MAGEL2 Fate in Human Neurons

Dr. Laugsch's group will examine the normal function of the MAGEL2 protein compared to MAGEL2 harboring SYS mutations, analyzing neuronal growth and function in the laboratory dish. Dr. Theresa Strong, Director of Research Programs, shares details on this project in this short video clip.

The Effect of Growth Hormone Treatment on Premature Aging and Quality of Life in Adults with PWS

In PWS individuals aged 40 and up, quality of life (QoL) seems to be mainly impaired by premature aging, and premature aging in PWS seems to be less prominent in adults treated with growth hormone (GH). This project will investigate whether GH indeed slows down premature aging in PWS, by using a lar...

Evaluating direct play intervention for preschoolers and long-term follow-up of the PRETEND program

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 establish...

Emergency Department and Inpatient Care of Individuals with PWS

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 c...

Transcriptome-wide identification and functional annotation of PWS-encoded SNORD targets

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...

The role of oxytocin receptor-expressing astrocytes in Prader-Willi and Schaaf-Yang syndromes (Year 2)

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...

Investigating the role of Snord116 in ribosome biology

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 t...

Postdoctoral Fellowship to Investigate the Molecular Biology of MAGEL2 in Schaaf-Yang and Prader-Willi Syndromes

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 bio...

Using Functional Near-Infrared Spectroscopy to Identify Biomarkers of Skin Picking Behavior in PWS

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)...

Application of Advanced Neuroimaging Techniques in Prader-Willi Syndrome

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 i...

Mapping the hypothalamic functional architecture underlying appetite control in the PWS brain

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 und...

Integration of Serum Metabolome and Gut Microbiome to Identify Host-Microbe Metabolic Interactions in PWS

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 metabolit...

Role of Microbial Metabolites in Regulating Hypothalamic Pathways Involved in Feeding Behavior

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 indiv...

The Prader-Willi PreClinical Animal Network (PCAN):Establishing a computational platform for the PCAN initiative

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 communit...

Wearable Device Use for Heart Rate Variability Measurement for Objective Assessment of Hyperphagia

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 op...

Deciphering the role of olfaction in Prader-Willi Syndrome

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 po...

MCH neuron dysregulation in the pathophysiology of Prader-Willi Syndrome

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....

Targeting SMCHD1 to address the underlying cause of PWS

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 fund...

Evaluation of CART as a potential therapeutic target for PWS using a rat model

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 inject...

The Role of Microglia in Prader-Willi Syndrome and a Hypothalamic Gene Therapy

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 stud...

Lived Experiences of Teens and Adults Who Grew Up With a Sibling Diagnosed With Prader Willi Syndrome

The PWS diagnosis impacts every person in the family. It changes family dynamics and relationships as well as every interaction with food. Siblings can be particularly vulnerable to the unavoidable stress related to managing and caring for a person with PWS. They may experience impacts in multiple a...

Determining beloranib’s mechanism of action to inform novel drug targets for Prader-Willi syndrome

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 ...

Preparatory studies to enable generation of a genetically engineered marmoset as a model system for Prader-Willi syndrome

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 gen...

Investigation of cerebellar control of striatal dopamine activity and food intake in PWS

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 t...

Advance Development of a Cell-Based Test for Screening of Drugs to Correct Circadian Rhythm Defects in PWS

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 development...

Delineating the role of MAGEL2 in impaired neurohormonal balance in PWS and SYS: Is there a way to overcome MAGEL2 requirement in hypothalamus?

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 f...

Noninvasive Neuromodulation of a Novel Cerebellar Satiety Circuit in PWS

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 impac...

shRNA/AAV9 Gene Therapy for the Treatment of Prader-Willi Syndrome

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. Dr. Theresa Strong, Director of Research Programs, shares deta...

PWS Smart-Start – A Randomized Clinical Trial

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 ...

In their own voices: Developing a self-report measure of Hyperphagia for Individuals with PWS

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-r...

Engineering epigenome editing tools for sustained reactivation of maternal PWS genes (Year 2)

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 mat...

Assessing DGKK Signaling Pathway as a SNORD116 Target in the Pathogenesis of PWS

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 hyp...

Role of fat sensing in the altered feeding behavior and metabolic phenotype of Prader-Willi syndrome

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 t...

Defining Cell-Type Specific Signatures and Dysregulated Pathways from Blood and Brain in PWS (Year 2)

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 i...

Targeting the orexin system to treat Prader-Willi syndrome associated hyperphagia

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 l...

Cellular and molecular basis for obesity in PWS

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 hyp...

Non-coding RNAs in neuronal differentiation and PWS

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...

Impairment of neuronal morphology and function in SNORD116 Prader-Willi syndrome mice

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 character...

Investigation of the Role of Fkbp5 to Induce PWS Phenotypes in a Magel2-null Mouse Model

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...

Prefrontal cortex MC4R neurons as a target for feeding and cognitive symptoms in PWS

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. Theresa Strong, Director of Research Programs, shares details on t...

MC3R inhibition as a therapeutic strategy for treating hyperphagia in Prader-Willi Syndrome

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. Theresa Strong, Director of Research Pro...

How does the epigenetic regulator SMCHD1 regulate the PWS cluster in humans?

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 m...

MAGEL2 role in adaptive stress response: New insights into MAGEL2 function and pathogenesis of PWS

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. Dr. Theresa Strong, Director of Research Programs, shares detail...

Where and when does SNORD116 interact with its mRNA targets?

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 underly...

Effects of Ultrasound Sensory Neuromodulation in Multiple Mouse Models of Prader-Willi Syndrome

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 ...

Impact of Bright Light Therapy on All-Cause Excessive Daytime Sleepiness in Prader-Willi Syndrome

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. Dr. Theresa Strong, Director of Research Programs, shares details on this project in this short vi...

Unraveling the mechanism of PWS by molecular dissection of driver genes in hypothalamic neuron model (Year 2)

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...

Genetic Determinants of Behavioral, Physical, and Physiological Characteristics of PWS

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 s...

Validation of a promising eye-tracking attentional bias paradigm as a biomarker for satiety in PWS

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 ...

Analysis of Delayed Neural Development in PWS DPSC Neurons

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 ther...

Comparative Behavioral and Proteomic Analysis of Rat Snrprn and Magel2 Models

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 pr...

Optimizing telehealth methods for identifying and treating distress among caregivers of individuals with PWS and WS

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 (William...

Planning Proposal to Add Angelman, Prader-Willi and Dup15q Syndromes to the Early Check Newborn Screening Panel

his 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 d...

Genomewide identification of mRNA sites of 2’-O methylation targeted by SNORD116 snoRNAs (Year 2)

In PWS, a cluster of small nucleolar RNAs (snoRNAs), the SNORD116 cluster, appears to be of critical importance, but the SNORD116 targets have yet to be identified. Dr. Carmichael and his team have engineered neurons that mimic naturally-occurring PWS deletions and are using them to look for alterat...

Developmental, behavioral, and metabolic characterization of the Necdin/Magel2 double knockout mouse

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 Ma...

Miniaturization of the PWS-domain for AAV-based genetic therapy in Prader-Willi syndrome (PWS)

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...

Elucidating PWS pathophysiology in patient derived 3D human cortical organoids

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 devel...

The role of oxytocin receptor-expressing astrocytes in Schaaf-Yang syndrome and Prader-Willi syndrome

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’ (astroc...

Long Non-Coding RNAs Transcribed From Prader-Willi syndrome Locus: Key Regulators of Gene Expression (Year 2)

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 ...

Gene Therapy of Obesity in Prader-Willi Syndrome by an Autoregulatory BDNF Vector (Year 2)

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 thera...

How is the Epitranscriptomic Signature of Active AGRP Neurons Disrupted in PWS?

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 proj...

Orphan GPCRS and the Neurobiology of Hyperphagia in Prader-Willi Syndrome: Role of GPR160

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, ...

Regulation of PWS Genes in the Endocrine Pancreas

ancreatic 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 ce...

Neurohormonal Controls of Energy Balance in the MAGEL2-Deficient Rat

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 tha...

Role of MAGEL2 in melanocortinergic circuits and feeding regulation

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 ...

Defining impaired neuronal architecture in the Snord116del mouse model for Prader-Willi Syndrome

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 th...

Guanfacine XR for Aggression and Self Injury in PWS A Double Blind Placebo Controlled Trial

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 guanfaci...

Unraveling the mechanism of PWS by molecular dissection of driver genes in hypothalamic neuron model

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 prop...

Gene Therapy of Obesity in Prader-Willi Syndrome by an Autoregulatory BDNF Vector

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 d...

Adult Spine Alignment in Prader-Willi syndrome

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 i...

Development of a suite of assays for the analysis of PWS patient iPSC-derived cortical neurons

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 drug...

A mouse model to assess genetic therapies for Prader-Willi syndrome (Year 2)

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 Role of the Placenta in PWS: Mapping the Expression of PWS Genes

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 o...

Assessment of Epigenetic Driven Circadian Rhythm Defects in Neurons from Individuals with PWS (Year 2)

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 cha...

Long Non-Coding RNAs Transcribed From Prader-Willi syndrome Locus: Key Regulators of Gene Expression

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 region...

Precise epigenome editing as a novel therapeutic opportunity for Prader-Willi syndrome

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 PW...

Identification of Critical Periods for the Neurodevelopmental and Behavioral Effects of Oxytocin (Year 2)

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 exer...

The Functional Development of Hunger Neurons in Prader-Willi syndrome (Year 2)

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...

Novel Transcriptomic Signatures in Blood and Brain Predictive of Behavioral Issues in PWS

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...

Role of MAGEL2 in Excitatory Synapse Function

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 Ma...

Investigation of Rapamycin as a Therapeutic Option in a Mouse Model of Schaaf-Yang Syndrome (SYS)

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 F...

Neuronal Mechanisms of Developmental Cognitive Impairment in the SNORD116Del Mouse Model for Prader-Willi Syndrome

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...

Improving Muscle Strength and Muscle Mass in People with Prader-Willi Syndrome

Dr. Shields is an expert in exercise programs for individuals with disabilities. Her team will evaluate progressive strength training as a means to improve muscle mass and function in individuals with PWS. Her goal is to develop online resources to help individuals with PWS optimize exercise and imp...

Allele-Specific DNA Replication Timing of the Prader-Willi Locus and its Influence on Neuronal Development

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 hypothes...

Role of Central Amygdala Anorexia Neural Circuits in Prader-Willi Syndrome

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 appeti...

Investigating the Cause of Mental Illness in PWS Using Magnetic Resonance Spectroscopy (MRS)

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 brai...

Cellular Role of MAGEL2 in Prader-Willi and Schaaf-Yang Syndromes (Year 2)

n 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 ...

A Mouse Model to Assess Genetic Therapies for Prader-Willi Syndrome

Genetic therapy has the potential to address the root cause of PWS, however, several feasibility questions need to be answered before we can consider genetic therapy for PWS. For example: Does activation of the PWS genes reverse symptoms in models of PWS? Which genes must be turned on? Does gene act...

Evaluating Endosomal Recycling Pathways in Primary Neurons from PWS Individuals (Year 2)

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 chi...

Role of the PWS Gene Magel2 in the Developing Hypothalamus

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 sequencin...

Investigating a New Potential Target for Treatment in Prader-Willi Syndrome

Dr. Rice and colleagues have shown that there is a decrease in GABA (a compound that helps turn brain activity off) in the brains of individuals with PWS, and this is associated with emotional problems, including a tendency for temper outbursts. In this project, the team will use brain imaging (fMRI...

Influences of Social Cognition and Reward on ASD Symptoms and Behavior in PWS

Social cognition, or the ability to understand the thoughts and feelings of others, is impaired in Prader-Willi syndrome. Social reward circuitry (which places value on things in our environment) may also be altered. This impairment may contribute to oppositional behavior and ASD symptoms, which are...

Enhancing Satiation Signaling to Reduce Overeating and Obesity in Prader-Willi Syndrome

Lack of satiety, or feeling 'full', is a hallmark characteristic of PWS. Satiety mechanisms are not well understood, and it is not clear how the stomach signals the brain to stop eating. It is believed, however, that the vagus nerve to hind brain connection (NTS) may be a key part of this mechanism....

The Functional Development of Hunger Neurons in Prader-Willi Syndrome

AgRP ('hunger') neurons are found in the hypothalamus and control feeding, metabolism and compulsive behaviors. There is evidence that AgRP neurons may be overactive during development in PWS, which might lead to some of the characteristics of PWS. In this project, Dr. Dietrich will use a cutting ed...

CRISPR-mediated molecular dissection of Prader-Willi syndrome

The PWS region of chromosome 15 consists of several genes. While we know the loss of all these genes together will lead to the characteristics of PWS, we still don’t know exactly what is the contribution of each gene. In this project, Dr Talkowski's team will use CRISPR technology (a very precise wa...

Genomewide identification of mRNA sites of 2’-O methylation targeted by SNORD116 snoRNAs

While we know the loss of SNORD116 (a gene that encodes many snoRNA molecules on Chromosome 15) leads to characteristics of PWS, we do not know how this exactly works. We need to understand how SNORD116 functions normally in order to understand why the loss of this region leads to PWS. It is likely ...

Targeting SMCHD1 to address the underlying cause of PWS and SYS

Associate Professor Blewitt and her research team study how genes shift between ‘sleeping’ to ‘awake’ states, and how this impacts a range of diseases. “A protein called SMCHD1 keeps many genes in their sleeping state,” Associate Professor Blewitt said. “We discovered that SMCHD1’s targets include s...

Identification of Critical Periods for the Neurodevelopmental and Behavioral Effects of Oxytocin

This grant supports a new collaboration between two scientists with complimentary expertise. Drs. Sebastian Bouret and Francoise Muscatelli will work to define critical periods for oxytocin use in PWS models, and optimize this therapeutic approach. Mouse models will be used to define the critical pe...

A transcriptome-wide approach to identifying RNA targets of the Prader-Willi locus snoRNAs (year 2)

Dr. Bratkovic has been working to identify the RNA targets of SNORD116 RNAs. His group is applying advanced techniques to examine the full complement of RNAs that interact with SNORD116 transcripts.

Improving social functioning in Prader-willi syndrome (year 2)

This project was funded by the Foundation for Prader-Willi Research UK.

Cellular role of MAGEL2 in Prader-Willi and Schaaf-Yang syndromes

Dr. Wevrick’s group has been studying the function of the MAGEL2 protein. This project focuses on one part of this protein, which the lab has recently found interacts with complexes that include specialized mRNAs. They will determine how MAGEL2 binding to these complexes influences the stability and...

Consequences of targeted SNORD116 deletion in human and mouse neurons

Dr. Yeo’s group has developed a mouse model of PWS that is based on loss of Snord116 after the newborn period, which results in an animal that more closely mimics the human condition, developing hyperphagia and obesity. Such an animal model will be important for testing new drugs. Here, they are usi...

Pig Models of Prader-Willi Syndrome for Pathophysiologic and Therapeutic Interventions

Dr. Nicholls has developed a large animal model of PWS (mini-pigs). The physiology and cognitive development of the pig are closer to humans and this may allow an improved model of understanding PWS and may facilitate the evaluation of new therapeutic interventions.

Evaluating endosomal recycling pathways in primary neurons from PWS individuals

Dr. Potts has identified a change in vesicle recycling in cells that have mutations in the MAGEL2 gene, as in Schaaf-Yang syndrome. Here, he will collaborate Dr. Larry Reiter, who has produced stem cell-based neurons from PWS ‘baby teeth’, to evaluate whether these same cellular changes are present ...

The gut microbiome in Prader-Willi syndrome

Dr. Costa-Mattioli has shown that the composition of the gut microbiome can influence autistic behaviors in mouse models, and that this influence acts through the oxytocin system. This study will examine Magel2-deficient mice and will focus on determining whether altering the gut microbiome can impa...

The molecular mechanism of SNORD116 action (year 2)

Dr. Stamm has been studying the normal function of the SNORD116 genes in PWS. In year 1, he has determined that SNORD116 plays a role in RNA stability, which may be important in controlling circadian rhythm and hormone release. In year 2 his group will examine how SNORD116 binds to these RNAs and co...

ComuFaces: The perception of communicative faces by infants with Prader-Willi syndrome (year 2)

This project was funded in partnership with FPWR-France

Assessment of Epigenetic Driven Circadian Rhythm Defects in Neurons from Individuals with PWS

Dr. Reiter is analyzing neurons, made from stem cells from individuals with PWS. He has noted disruptions in the circadian rhythm of these cells (day/night cycle) that may reflect sleep problems in PWS. His work will identify how the circadian rhythms are disrupted in PWS cells, and pave the way for...

Understanding the Role of Microglia in the Prader-Willi Hypothalamus

Dr. Kurrasch is studying whether inflammation in the brain, mediated by special immune cells called microglia, might contribute to hyperphagia and obesity in PWS. Using a mouse model of PWS, she will examine microglia activity and explore whether eliminating microglia improves energy regulation. Fun...

Newborn Screening for Prader-Willi and Angelman Syndromesc

Universal newborn screening for PWS will ensure that all babies with PWS are diagnosed at birth. Dr. Godler has developed a sensitive, accurate and cost-effective DNA test for detection of PWS and Angelman syndrome using the bloodspots (“heelprick”) obtained in all newborns. In the study, FPWR is co...

Cannabidivarin (CBDV) vs Placebo in Children with PWS

This grant will support a small clinical trial evaluating the impact of cannibidiol cannabidivarin (CBDV) on hunger and behavior. CBDV is a compound similar to CBD, but with potential advantages over CBD for PWS. In this study, Dr. Hollander’s group will investigate a form of CBDV, a non-psychoactiv...

Design and Implementation of Hypothalamus-Specific Exosomes to Restore SNORD116 Deletion in PWS

Dr. Lee’s group is exploring the use of a novel gene transfer vehicle, exosomes, to deliver missing portions of the PWS genes to the hypothalamus. In this pilot study, they seek to develop PWS-specific exosomes and test how well these can deliver genes to neurons and other cells. Theresa Strong, Dir...

Acceptance and Commitment Training (ACT) to Reduce Stress in Fathers of Adolescents with PWS

Families of those with PWS experience a great deal of stress, particularly during adolescence. In this study, we are funding the development of a new behavioral intervention, aimed at developing more effective coping skills in fathers of adolescents with PWS, as a means to improve overall family wel...

Generation of Non-Human Primate Models of PWS

This project takes the first steps towards developing a primate (macaque) model of PWS. Animal models of PWS are currently limited and are not able to replicate some important aspects of PWS, such as intellectual disability, as well as behavioral and social impairments. These aspects of PWS may be m...

Chronic Stress, Cognition, and Food Cue Reactivity in PWS. A Magnetoencephalography Study

This study will combine advanced brain imaging technology with other assessments to examine how hormonal, cognitive, and psychological factors are interrelated in PWS. Results from this study will increase the understanding of how brain regions involved in food intake are related to appetite hormone...

Cannabinoid-1 Receptor Blockade to Treat Hyperphagia, Obesity and Related Metabolic Disorders in PWS

This grant supports the development of a new drug to tackle hunger and obesity with PWS. Inversago, a newly started, specialized biotech company, proposes that its CB1 blockers would treat a wider spectrum of symptoms than anything presently in development for PWS. The drug targets the endocannabino...

The SNORD116-NHLH2 pathway: insights into the molecular genetic basis of Prader-Willi Syndrome

Dr. Good is an expert on the gene, NHLH2, which was recently implicated in the underlying the cellular changes present in PWS. Loss of the PWS-region gene, SNORD116 causes a reduction in the activity of NHLH2, which normally regulates expression of the gene PCSK1, also implicated in PWS. Here, the l...

Dissecting a novel brainstem feeding circuit in Prader-Willi syndrome

This project was funded by the Foundation for Prader-Willi Research Canada.

A mindfulness-based intervention for temper outbursts in Prader–Willi syndrome

This project was funded by the Foundation for Prader-Willi Research Canada

A post-mortem study of von Economo neurons in the frontal cortex of brains of persons with PWS (year 2)

This project is examining a specialized kind of neuron that is important in social interaction, to determine whether these neurons they are altered in the brains of individuals with PWS. In year 2, additional studies on new samples will be undertaken, with accompanying protein analysis.

Developing objective biomarkers of hyperphagia in children with PWS

This proof of concept study will determine whether ‘eye tracking’ and brain-based ‘event related potential’ measures will be useful as clinical trial endpoints. These approaches might objectively and quantitatively measure a participant’s interest and focus on food.

Prevalence and aetiology of PWS low level mosaicism in UPD undetected by standard testing

This team has found that some individuals with PWS by UPD actually have some cells with that have three chromosome 15s (trisomy 15). Here they will examine this in a larger group of patients, and look at how the clinical characteristics and severity of PWS symptoms might be influenced by this phenom...

Role of the endocannabinoid system in PWS-induced osteoporosis and skeletal growth

This group will examine whether pharmacological targeting of CB1R improves osteoporosis in PWS. This preclinical work, using the Magel2 PWS mouse model, will define the underlying basis of osteoporosis and evaluate whether a new drug, previously shown to reduce weight in PWS mice, will also increase...

Systematic Investigation of Early Social Cognitive Processes and the Feasibility of Intervention

This project was funded by the Foundation for Prader-Willi Research Canada

Neural mechanisms of oxytocin-enhanced infant feeding and social behavior development

Dr. Hammock is an expert in the neurobiology of social behavior. This project will examine how oxytocin receptors in the nose and mouth respond to oxytocin, defining the mechanisms that drive the effectiveness of intranasal oxytocin as a therapy for feeding and social behaviors in PWS, thus optimizi...

CRISPR-mediated 3D modeling, molecular dissection and epigenetic profiling of PWS

The Talkowski lab focuses on the use of cutting edge CRISPR technology to develop advanced cellular models of neurodevelopmental disorders. They will engineer precise disruptions of the PWS region, followed by detailed cellular analysis, to better understand the contributions of the different genes ...

Examination Of Incidence Of Individuals With PWS Undergoing Total Hip and Knee Arthroplasty

Hip dysplasia is relatively common in PWS, yet there is no consensus among experts on whether it should be treated surgically. This large scale review of medical records will examine outcomes of hip dysplasia surgery in PWS, and will guide the development of recommendations on how best to treat hip ...

Therapeutic Potential of Blocking Zinc Finger Protein 274 Binding to the PWS Locus

This project was funded by the Foundation for Prader-Willi Research Canada

Evaluating factors that may affect the efficacy of intranasal oxytocin treatment in PWS

To date, clinical trials with intransal oxytocin treatment in PWS have yielded inconsistent, and in some instances, contradictory results on PWS specific behaviors, appetite and socialization. It’s not yet clear why some individuals respond positively to OT therapy and some don't, and determining ge...

Gene Expression Analysis in PWS Subject Derived Dental Pulp Stem Cell Neurons (year 2)

Dr. Reiter has expertise in disorders of chromosome 15, including chromosome 15 duplication syndrome. He will study neurons derived from ‘baby teeth’ from PWS and other 15q disorders, to identify genetic changes that might be contributing to features of autism in PWS.

Transcranial direct current stimulation, startle modulation and event-related potentials of the brain

Dr. Butler’s group has done a preliminary study suggesting that a weak, noninvasive form of brain stimulation, transcranial direct current stimulation (tDCS), may offer a new approach to reduce food cravings and overeating in PWS. Here, the research team will evaluate tDCS in 20 adults with PWS, mea...

Proof of concept study of vagus nerve stimulation from an external device in PWS (year 2)

Dr. Holland did a small pilot study on the use of VNS in PWS, and found an unexpected beneficial effect on behavior. Here he will do an expanded clinical trial, using a new, noninvasive device, and measure effects on behavior.

Small molecule allosteric modulators of the melanocortin-4 receptor for the treatment of Prader-Willi syndrome

There is some data suggesting that one of the systems that regulates appetite and weight in the brain, the melanocortin-4 receptor pathway, may be disrupted in PWS. This study will examine a new class of drugs targeting this pathway, in a mouse model of PWS. The drugs will be tested alone and in com...

Wake promoting effects of oxytocin

Caregivers, physicians and patients with PWS report that daytime sleepiness in PWS significantly disrupts daily life. However, the underlying cause of excessive daytime sleepiness in PWS is unknown. Dr. Scammell’s group is exploring the contribution of reduced neuronal function in the hypothalamus r...

Recapitulating obesity and hyperphagia in novel adult-onset mouse models of Snord116 deletion

Although it is well established that deletion of SNORD116 contributes to PWS in humans, mice missing Snord116 don’t display hyperphagia and obesity. This makes it very difficult to study the biology of SNORD116 and test anti-obesity drugs. In a major breakthrough, Dr. Yeo’s group has shown that if S...

Understanding multiple hormone secretion deficits in Prader-Willi Syndrome

Numerous hormone levels are deficient in PWS. However, the underlying biology and how the altered hormone levels contribute to the characteristics of PWS is not well understood. Dr. Nicholls’ group has developed a novel cell culture model system to study how PWS genes regulate hormone production and...

Ghrelin: Is it detrimental, beneficial, or inconsequential in Prader-Willi Syndrome? (year 2)

Ghrelin levels are elevated in PWS, but why, how, and whether it plays a role in hyperphagia or other aspects of PWS are all still unanswered questions. This project will explore if ghrelin plays a protective role in PWS with regards growth hormone deficiency, hypoglycemia and mental health issues, ...

Reactivation of the PWS locus via disruption of the ZNF274 silencing complex (year 2)

In year one of support, Dr. Lalande and his group characterized the role of a regulatory protein, ZNF274, in silencing the PWS region on the maternal chromosome, and demonstrated that disruption of ZNF274 causes reactivation of the PWS genes. Here they will extend that work and evaluate advanced met...

The MAGEL2 phenotype in comparison to classic Prader-Willi syndrome

Loss of the PWS region gene, MAGEL2, has recently been described by Dr. Schaaf, and associated with many of the characteristics of PWS. Here, Dr. Schaaf will examine in detail the behavioral, cognitive, and endocrine characteristics of ten individuals with mutations in the MAGEL2 gene only in compar...

Physiological and genetic determinants on hyperthermia and hyperphagia in PWS

Dr. Tucci’s group has shown that mice with the SNORD116 deletion have sleep abnormalities and increased body temperature. They hypothesize that environmental temperature may play a crucial role in the pathophysiology of PWS symptoms including sleep and obesity. They will use PWS mice that will be ma...

Improving social functioning in Prader-Willi syndrome

People with intellectual or developmental disabilities, including Prader-Willi syndrome (PWS), are at heightened risk for social exclusion and isolation. This underpins loneliness, depression and anxiety, contributes to poor health and reduced longevity. This project will recruit 50 young adults wit...

The molecular mechanism of SNORD116 action and possible SNORD116 substitution strategies

The loss of two snoRNAs, SNORD115 and SNORD116, plays a central role in the development of Prader-Willi syndrome. However, the normal function of SNORD116 is still unclear, making it difficult to understand what goes wrong when SNORD116 is lost. Dr. Stamm’s group is exploring how SNORD116 influences...

Preclinical studies of a novel epigenetic therapy for Prader-Willi syndrome

Dr. Jiang has identified a drug that can activate the maternal PWS genes. Next step in advancing small molecules for gene activation; builds on previous project to identify drugs; addresses basic question about feasibility of activating silenced genes

Impact of carbohydrate restricted diet upon growth and hyperphagia/food anxiety in childr en with Prader-Willi syndrome

Dr. Scheimann will be studying the effects of a carbohydrate restricted diet in school age children with PWS. Dr. Scheimann will examine the impact of a modified Atkins diet on growth, weight, anxiety and hyperphagia. *Funded by FPWR-Canada

Loss of MAGEL2 and hypotonia in Prader-Willi syndrome

Dr. Wevrick’s group has found that mice missing the PWS-region gene Magel2 have reduced strength, activity levels and endurance. In this study they will examine interventions including diet, supplements and drugs, to improve hypotonia and muscle strength and endurance. The goal is to identify interv...

Mitochondrial Complex I dysfunction in Prader Willi Syndrome: A new therapeutic target

Dr. Tein is an expert in energy metabolism and muscle fitness, who is examining mitochondrial dysfunction in PWS. Her group will carefully study the effects of CoQ10 in adolescents with PWS, measuring effects on strength, endurance, muscle function. This study should provide important guidance on us...

A post-mortem study of von Economo neurons in the frontal cortex of brains of persons with PWS

Dr. Hof is an expert in neuroanatomy. He will study the structure and distribution of type of neuron (von Economo neurons) that are critical for sensory awareness, social interaction, and problem solving. These neurons are disrupted in other disorders such as autism, but have not yet been studied in...

Plastic TASTER: a switching training game for people with PWS that adapts to individual needs (year 2)

Dr. Woodcock is interested in understanding the underlying triggers for temper tantrums in PWS, and has identified ‘task switching’ as a significant challenge. This project aims to develop a software prototype directed at teaching and improving task switching in PWS. In year 2, development of the pr...

Predictors of psychosis in Prader Willi Syndrome

Dr. Bearden focuses on identifying the earliest (‘prodromal’) phase in the onset of mental illness. Here she will apply the lessons from other populations to better define the predictors of impending mental illness in PWS. They will evaluate an online assessment approach to determine the cognitive p...

Oxytocin treatment in Magel2-deficient mice (year 2)

Dr. Muscatelli will continue her work developing novel mouse models to investigate how early treatment of a PWS mouse with oxytocin results in improvements in feeding, cognition and social interaction. Using advanced genetic engineering, she will investigate the interaction of the PWS region gene, M...

Methylation test validation for combined Prader-Willi and Fragile X syndrome newborn screening

Dr. Godler is developing a cost-effective test to be incorporated into newborn screening, which may allow accurate and early diagnosis of all babies with PWS.

Rapamycin treatment to correct the circadian mTOR imbalance in the Snord116 deletion mouse model of PWS

Dr. LaSalle has identified a defect in circadian rhythm genes in PWS. Here she will see if a common drug, rapamycin, can correct that defect in a mouse model of PWS.

ComuFaces: The perception of communicative faces by infants with Prader-Willi syndrome

Infants with PWS seem to pay less attention to external stimulations and have delayed social, emotional and linguistic skills. Dr. Barone’s group will explore how infants with PWS perceive communicative faces, a critical component of language, social, and cognitive development. This study will be th...

The role of SNORD116 in the neuroendocrine phenotypes of Prader-Willi syndrome

Dr. Leibel’s group has been using PWS induced pluripotent stem (iPS) cells to investigate how loss of the critical SNORD116 genes in the PWS regions leads to the characteristic of PWS. Their work suggests a common underlying mechanism responsible for many of the neuroendocrine disruptions. Here they...

Evaluating the Parent-focused Remote Education To Enhance Development (PRETEND) Program in PWS

This project will focus on understanding the social-cognitive phenotype of PWS, and will evaluate an educational program to optimize learning, play, and joint engagement between young children with PWS and their parents.

Activation of silenced genes in Prader-Willi syndrome

This project will use cutting-edge CRISPR technology to evaluate the feasibility of activating the silenced genes in the PWS region. Successful completion of the goals will be a first step to genetic therapy.

Proof of concept study of vagus nerve stimulation from an external device In Prader Willi Syndrome

Dr. Holland did a small pilot study on the use of VNS in PWS, and found an unexpected beneficial effect on behavior. Here he will do an expanded clinical trial, using a new, noninvasive device, and measure effects on behavior.

Investigating neural development in an induced pluripotent stem cell model of Prader-Willi Syndrome

The Ming laboratory studies the characteristics of neurons derived from individuals with mental illness, examining changes at the cellular level. They will derive neurons from the skin cells of individuals with PWS and elucidate cellular changes. This represents the first step in screening molecules...

RNA targets of SNORD116

Loss of the SNORD116 genes on chromosome 15 appears to be critical for the development of PWS, and, to date, how these genes normally work is poorly understood. Dr. Bratkovic will apply a novel technology to understand the function of this unusual class of genes.

Oxytocin and the autonomic nervous system in Prader Willi syndrome

Dr. Einfeld will work with a team with experts on oxytocin (Dr. Sue Carter) and the autonomic nervous system (Dr. Steve Porges) to investigate disruptions of these systems in PWS and lay the groundwork for informative clinical trials. (Partially funded by FPWR-UK)

Gene Expression Analysis in PWS Subject Derived Dental Pulp Stem Cell Neurons

Dr. Reiter has expertise in disorders of chromosome 15, including chromosome 15 duplication syndrome. He will study neurons derived from ‘baby teeth’ from PWS and other 15q disorders, to identify genetic changes that might be contributing to features of autism in PWS.

Development and validation of ghrelin O-acyltransferase inhibitors for treating hyperphagia in Prader-Willi syndrome

Dr. Hougland is continuing studies to develop a novel class of drugs that disrupts ghrelin in PWS. In the second year, he will optimize the inhibitors and test them in cells.

Role of melanin concentrating hormone in an animal model of Prader-Willi Syndrome

Melanin concentrating hormone (MCH) is an important regulator of appetite in the brain, but it has not been studied in PWS. This study will examine whether this brain chemical is disrupted in a mouse model of PWS. (Funded in partnership with FPWR-Canada)

Characterisation of anti-ghrelin autoantibodies in Prader-Willi Syndrome

Dr. Chopin’s studies suggest individuals with PWS may have antibodies to ghrelin that contribute hunger. Here she will study those antibodies in depth and determine whether they are contributing to increased appetite (Funded by FPWR Canada)

Regulation of ghrelin and serotonin receptors by SNORD115

The biological mechanism for low levels of growth hormone in PWS remains unknown. This group hypothesizes that the underlying cause is a cascade effect from the PWS gene SNORD115 → the serotonin receptor → growth hormone release. The results from this project could offer a new avenue for treating ho...

Biological and molecular functions of PWS-encoded small nucleolar RNA genes

The role of the PWS gene SNORD116 is known to be critical, but how is still not understood. This group proposes that SNORD116 snoRNAs may have a role in the production of ribosomes, a key piece of machinery in cells required for protein production. Their study will shed light on why loss of SNORD116...

Reactivation of the PWS locus via disruption of the ZNF274 silencing complex

This project was funded by the Foundation for Prader-Willi Research Canada

Ghrelin: Is it detrimental, beneficial, or inconsequential in Prader-Willi Syndrome?

Ghrelin levels are elevated in PWS, but why, how, and whether it plays a role in hyperphagia or other aspects of PWS are all still unanswered questions. This project will explore if ghrelin plays a protective role in PWS with regards growth hormone deficiency, hypoglycemia and mental health issues, ...

Linking the cellular function of MAGEL-2 to its role in PWS

In order to function properly, proteins not only have to be expressed at the correct levels, they have to be in the right place in the cell to do their job. This group will explore the role that the PWS gene MAGEL2 has on protein trafficking in neurons of the brain. Results from this project could p...

Mechanisms of sleepiness and other sleep abnormalities in a mouse model of Prader-Willi Syndrome

This group has expertise in sleep physiology and will explore the mechanism of daytime sleepiness and cataplexy in PWS. They hypothesize that lower levels of oxytocin neurons and orexin signaling contribute to these issues. These experiments will provide insights into how changes in the hypothalamus...

Role of the lipid-derived satiety factor, oleoylethanolamide, in PWS

Oleoylethanolaminde (OEA) is a hunger-reducing signal generated by the body. This study will examine the presence and function of OEA in a PWS mouse model and in people with PWS.

Development of appetite-related neural circuits in a mouse model for PWS (year 2)

Dr. Bouret’s group has previously shown that abnormally elevated levels of the gut-hormone ghrelin and loss of Magel2 can both impact normal development of hypothalamic neurons. This impacts key physiological processes including appetite regulation. In year 2, his group will explore the mechanism be...

The role of PREPL in the pathophysiology of PWS: evaluation of a novel therapeutic approach for the treatment of hypotonia

Dr. Creemers’ group has identified deficiency in the enzyme PREPL as a possible contributing factor to hypotonia in PWS. This study will test whether treatment with the antibiotic sulfamethoxazole will improve neuromuscular transmission and muscle function in a mouse model of PWS and in infants with...

Evaluation of autism-like behaviors in mice deficient for Magel2

Dr. Schaaf and co-workers recently identified mutations of the MAGEL2 gene in individuals showing many features of PWS, including autism. Here he will study the Magel2 deficient mice to see if they reflect the behavioral changes seen in humans. This study will provide the foundation for evaluating t...

Gut microbiome in individuals with PWS

We each carry a large and diverse population of bacteria in our gut, collectively called the “gut microbiome”. These bacteria vary among individuals, are critical to normal gastrointestinal function, and can be manipulated by diet and supplements. There is an emerging field of research exploring how...

Transcranial direct current stimulation, startle modulation and event-related potential of the brain to evaluate hyperphagia in PWS

Dr. Butler’s group has done a preliminary study suggesting that a weak, noninvasive form of brain stimulation, transcranial direct current stimulation (tDCS), may offer a new approach to reduce food cravings and overeating in PWS. Here, the research team will evaluate tDCS in 20 adults with PWS, mea...

Injectable protein gene activation therapy for PWS (year 2)

Building on efforts to reactivate the maternal allele in PWS, Dr. Segal’s group is designing injectable proteins targeted at turning on the maternal SNORD116 cluster and Magel2 gene. These funds will help test the effectiveness of the proteins in a mouse model of PWS. A rat model of PWS will also be...

Investing in Young Investigators

Small molecules and therapeutic potential for PWS

All individuals with PWS have a set of normal genes on their maternally-derived chromosome, but the genes in the PWS regions are ‘silent’. Dr. Jiang will screen a library of 10,000 small molecules to identify candidate drugs that can reactivate the PWS region genes on the maternal chromosome 15, spe...

The role of SNORD116 in Prader-Willi syndrome (year 2)

This project is a continuation of a study examining the consequences of loss of the SNORD116 genes in iPSC neurons derived from PWS microdeletion patients and unaffected individuals. The research team will explore the downstream effects of SNORD116 loss on cellular function.

Training task switching to decrease temper outbursts in people with PWS

Individuals with PWS have a strong preference for routine and predictability, with changes or “task-switching” often being a major trigger for temper outbursts. This project aims to develop a software prototype directed at teaching and improving task switching in PWS. If successful, this could be th...

Genome-wide survey of DNA methylation in PWS

Methylation patterns of an individual’s entire genome have a profound impact on overall gene expression and, in turn, the function of every body system. Dr. Kim’s group will explore whether the genetic and epigenetic alterations in the PWS region also impact the overall global genomic DNA methylatio...

Nutritional aspects of PWS and childhood obesity: a metabolomics approach

Hyperphagia and food related behaviors in PWS have been classified into six distinct nutritional phases. However, the mechanism(s) underlying these phases and what triggers the transition from one phase to another remains poorly understood. Dr. Driscoll’s group will use analyze differences in specif...

How does oxytocin cure early feeding and adult social behavior alterations in Magel2 deficient mice, a model for the PWS?

Dr. Muscatelli’s group has shown that administering a single dose of oxytocin to the Magel2 deficient mouse model of PWS at birth can restore suckling activity as pups and improve social behavior as adults. The group will now examine the mechanisms behind this effect to help define the relationship ...

Comprehensive behavioral informatics approach to CNS function in PWS mouse models

In recent years, several new mouse models for PWS research have been developed. These PWS mice are valuable tools for testing potential therapeutics on PWS-related behaviors. To efficiently evaluate therapies in these animals, standardized assessments of behavior are needed. Dr. Tecott’s group has e...

Inhibitory circuits and transmission in the hypothalamus in a mouse model of PWS

Using advanced neurobiology techniques and the Magel2 knockout mouse model of PWS, Dr. Stuber’s group will be characterizing the distribution of Magel2 throughout regions of the brain and the role of Magel2 in neurotransmissions related to hyperphagia. These studies will help map the neurocircuitry ...

Unraveling the developmental neurobiology of PWS: a cross-sectional brain-imaging study (year 2)

These researchers will use advanced brain imaging techniques in combination with clinical data to better understand psychiatric problems in PWS. The goal is to identify markers for early detection of mental health problems to allow more timely and effective intervention.

A Dose Titration Study of Diazoxide Choline Controlled-Release Tablet (DCCR) in Patients with Prader-Willi syndrome with a Double-Blind, Placebo-Controlled, Randomized Withdrawal Extension

Diazoxide is an FDA approved drug that has effects on energy expenditure and appetite. It has not yet been studied in PWS. We will partner with the company Essentialis to support the evaluation of this drug in children and young adults with PWS, to determine the drugs effects on hyperphagia and ener...

The role of SNORD116 in Prader-Willi syndrome

This project is a continuation of a study examining the consequences of loss of the SNORD116 genes in iPSC neurons derived from PWS microdeletion patients and unaffected individuals. The research team will explore the downstream effects of SNORD116 loss on cellular function.

Oxytocin vs. placebo for the treatment of hyperphagia in Prader-Willi syndrome

(Best Idea Grant in partnership with PWSA(USA)). This study will explore the potential benefit of intranasal oxytocin (OXT) treatment on behaviors in children and adolescents with PWS, specifically those with symptoms of ASD.

Investigation of ghrelin-o-acyltransferase as a target for treating hyperphagia in Prader-Willi syndrome (Year 1)

(Best Idea Grant in partnership with PWSA(USA)). Elevated levels of the hormone ghrelin may be a major contributor to hyperphagia in PWS. Dr. Hougland’s team will use synthetic chemistry to develop molecules targeted at reducing ghrelin O-acyltransferase (GOAT) activity, an enzyme required for prope...

Support to develop a grant application for a cross-over controlled trial of vagus nerve stimulation (VNS) in PWS

Dr. Holland, a psychiatrist specializing in intellectual disabilities and President of PWSA-UK, has encouraging pilot data evaluating the benefits of vagus nerve stimulation (VNS) in PWS. These funds will help Dr. Holland and his team prepare materials to compete for a large grant to support a clini...

Early to midterm oxytocin effects on the brain metabolism of adults with Prader-Willi syndrome (year 2)

A continuation of Dr. Tauber’s study to evaluate the effects of repeat oxytocin delivery in adults with PWS. This project was funded in collaboration with Prader-Willi France.

Unraveling the developmental neurobiology of PWS: a cross-sectional brain imaging study

These researchers will use advanced brain imaging techniques in combination with clinical data to better understand psychiatric problems in PWS. The goal is to identify markers for early detection of mental health problems to allow more timely and effective intervention.

Functional Assessment of snoRNA derived microRNAs in Prader-Willi Syndrome

We still don’t understand how loss of the snoRNAs on chromosome 15 leads to PWS. These researchers will combine bioinformatics and molecular genetics to study a new class of RNAs (microRNAs) that are produced from those snoRNAs, which may play a critical role in regulating genes that determine the P...

Osteoporosis in individuals with PWS and the role of vitamin D receptor

This study will identify genetic variants (outside of the PWS region) that may determine those with PWS who are at particularly high risk of developing osteoporosis. This has the potential to impact what drugs are considered to prevent/treat osteoporosis on an individual basis.

Clinical trials initiative

Dr. Miller is assisting FPWR in identifying opportunities for clinical trials in PWS and developing recommendations for the conduct of such clinical trials. She is also aiding in the development and implementation of the Global PWS Registry.

European PWS blood bank coordinator

Dr. Tauber is leading a European effort to collect blood samples on infants and children with PWS to monitor changes in hormones over time. This funding supports a blood bank coordinator to collect clinical data on birth, growth, endocrine functions and feeding behavior in newly diagnosed patients w...

Understanding the Neurobiology of Temper Outburst Behaviors in Prader-Willi Syndrome

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.

Establishment of an in vitro model of muscle cells derived from primary fibroblasts to study dysregulation of translational capacity in PWS

Previous results showed that our physical rehabilitation program could induce weight loss in a group of adult PWS patients, but failed to improve their muscular mass (Grolla et al.2010). The loss of muscle mass affects elderly, obese and PWS patients leading to frailty and impaired quality of life. ...

Hypoglycemia in PWS: A prospective study

A retrospective study has indicated that infants with PWS may have detrimental episodes of very low blood sugar. Here, the investigators will examine the prevalence and nature of hypoglycemia in infants with PWS.

Neurobiology of temper outburst behaviours in Prader-Willi syndrome - imaging pilot study

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.

Oxytocin actions of prefrontal cortex circuits in a mouse model of Prader-Willi Syndrome

Investigators have identified a set of neurons that are responsive to oxytocin in the prefrontal cortex. Here they will study them in normal mice and mice missing Magel2, a key gene in the PWS region. The goal is to better understand how oxytocin normally functions in the brain and what the effects ...

Targeting the peripheral endocanniabinoid system for the treatment of obesity in a mouse model of PWS

Dr Tam is working on development of a novel anti-obesity drug – a version of this drug showed positive effects in PWS but was not tolerated due to effects on mood/emotional stability. This version doesn’t get into the brain (reducing the likelihood of behavioral side effects) but can still produce w...

Evidence based approach to dietary management of PWS

Drs. Haqq and Freemark will collaborate to apply new ‘proteomic’ techniques to examine how diet modifies the metabolism (metabolomics). They will compare the metabolic profiles of PWS subjects on low carb versus low fat diets to identify a favorable metabolic parameters and inform diet selection.

Allele specific regulation of SNORD116 in PWS

Dr. Martins-Taylor is a young investigator just starting out on her career. She will perform molecular genetic study to understand why maternal and paternal chromosome 15s behave differently, using induced pluripotent stems cells from individuals with PWS. The findings of the study have implications...

The role of the prefrontal cortex in PWS hyperphagia

Dr. DiLione is a highly respected investigator in the area of food reward pathways. The investigators will look at PWS mouse models and use cutting edge imaging techniques to define the brain circuits controlling motivation to eat.

Use of stem cell-derived neurons to identify the molecular basis of the PWS

Stem cell technologies enable researchers create a cellular model of disorders, sometimes called “disease in a dish”. Dr. Leibels’ group will transform skin cells from PWS patients into pluripotent stem cells (iPS). The iPS cells can be differentiate into brain cells (neurons) and used to characteri...

Reactivation of maternally-silenced genes in PWS

This proposal will investigate the development of a gene therapy for PWS. Dr. Segal’s group works on engineering proteins to activate specific genes. He will apply this technology to the PWS region to unsilence the maternal PWS genes, and test the approach in a mouse model of PWS. This work is an im...

Early to midterm oxytocin effects on the brain metabolism of adults with Prader-Willi syndrome

Development of appetite-related neural circuits in a mouse model for Prader-Willi syndrome (year 1)

Many key physiological processes, including appetite regulation, are established during the perinatal period. Babies with PWS display abnormally elevated levels of the gut-hormone ghrelin. Dr. Bouret has found that high levels of ghrelin impact the development of the hypothalamus. The goal of this r...

Pancreatic and neuro-endocrine cell secretory pathway deficits in PWS

This project will examine PWS region genes to determine how they exert control over production of hormones in specialized neuroendocrine cells, and how this is disrupted in PWS. Dr. Nicholls hypothesizes that abnormal functioning affects the metabolic balance and directly leads to problems in glucos...

Small molecular screening and therapeutic potential for PWS

All individuals with PWS have a set of normal genes on their maternally-derived chromosome, but the genes in the PWS regions are ‘silent’. Dr. Jiang will screen a library of small molecules to identify candidate drugs that can reactivate the PWS region genes on the maternal chromosome 15. Promising ...

Development of leptin dysregulation in a mouse model of obesity in PWS

The investigator has previously shown mice missing the PWS-region gene Magel2 are obese and have hypothalamic neurons that are unresponsive to leptin. Here, they will examine whether mice lacking Magel2 are unresponsive to leptin from birth, or whether insensitivity happens gradually. They will test...

Nutritional aspects of Prader-Willi syndrome and childhood obesity: correlation of plasma orexin levels with nutritional phases

Orexin is a hormone that promotes wakefulness and appetite. The investigators hypothesize that blood orexin levels change over time in individuals with PWS as they transition through the nutritional phases, and that low orexin levels cause excessive sleepiness and obesity by decreasing the metabolic...

A pig model of PWS: a breakthrough for obesity, clinical and therapeutic studies

Dr. Nicholls will tackle the ongoing challenge of developing a good animal model of PWS by looking to a new species, the pig. Recent advances in genetic technology now allow this species to be investigated as models of rare genetic disorders. With this support, Dr. Nicholls will initiate the develop...

Role of SNORD116/HBII-85 snoRNAs in Prader-Willi syndrome

Dr. Yeo will study the genetic region that is critical in PWS, the “snoRNAs”. He will use a variety of biochemical techniques to determine the normal biological function of these RNAs, which is currently unknown. He will also examine the potential role of the snoRNAs in the brain during fasting peri...

Environmental, physiological and neural bases of skin picking in Prader-Willi syndrome

Dr. Hall and his group will be investigating the causes of skin picking in PWS, using state-of-the-art behavioral and neuroimaging methods. He will systematically analyze the environmental, physiologic and neural contributors to skin picking in individuals with PWS.

Generating a novel model of ghrelin-null Prader-Willi syndrome

Dr. Wells will use an existing PWS mouse (the IC del mouse) to investigate the role of ghrelin in driving hunger and taste preferences in PWS. In work that was recently recognized at an international meeting, Dr. Wells’ group showed the PWS ICdel mouse had altered food reward motivation and increase...

A Prader-Willi syndrome mouse model with brain specific ablation of snoRNA clusters from the Snrpn to Ube3a region

Dr. Jiang brings expertise in PWS and Angelman syndrome (AS) to develop a PWS mouse model that specifically deletes the PWS critical region in the brain at designated times during development. This genetic manipulation of the PWS mouse may allow the mice to survive the newborn period and manifest th...

Longitudinal investigation of pubertal development and reproductive hormones in Prader-Willi syndrome from infancy through adulthood (year 2)

Dr. Gross-Tsur and colleagues, with a second year of support from FPWR, will continue studies on their PWS population to gain an understanding of reproductive hormones over time. The information gained from their study will be useful in developing clinical guidelines to help individuals with PWS thr...

Role of Kiss1 neurons in mediating grhrelin’s effect on effect on reproduction and metabolism (year 2)

Dr. Elias has been investigating how high levels of ghrelin in PWS might affect sexual development and metabolism. In year 2 of support she will continue these studies, examining how a particular group of neurons, critical to regulating puberty and metabolism, are altered in their function by abnorm...

Mechanism of hyperphagia and therapeutic interventions in mouse models for Prader-Willi syndrome

Dr. Ding will use a mouse model of PWS to examine the role of ghrelin and the nervous system in promoting hunger in PWS. She will examine ways to block ghrelin action to investigate potential new therapies for PWS.

Characterization of skeletal muscle abnormalities in mouse models of Prader-Willi syndrome: Functional role of Necdin?

Dr. Cohn is an expert in hypotonia, and his research focuses on how muscle mass is developed and maintained. He will investigate how muscle is different in PWS compared to normal and the cellular and molecular level, and explore the role of the PWS-region gene, necdin, in PWS muscle abnormalities.

R-loop formation and chromatin decondensation at the PWS critical locus

Dr. LaSalle’s studies have focused on understanding how the maternal and paternal chromosomes differ in the PWS region of chromosome 15. This region is characterized by unusual DNA and RNA structures, and this study seeks to understand how the structures develop and what their impact is on the devel...

Longitudinal study of reproductive hormones in Prader-Willi syndrome from infancy through adulthood

Dr. Hirsch and colleagues have recently published studies providing the first understanding of incomplete sexual development in PWS. Here, they will follow hormone changes in the same individuals over time. These studies will be useful in determining recommendations for hormone therapy in PWS.

The relationship between serum brain-derived neurotrophic factor (BDNF) levels, BDNF haplotypes and neurocognitive performance in children with PWS

Dr. Haqq and colleagues recently reported that children with PWS may have low levels of BDNF, which can contribute to a variety of problems including decreased cognitive abilities. This study will expand that initial investigation, and look specifically at how cognitive abilities relate to BDNF leve...

The 5-HT2CR: Mining a new experimental approach to therapeutics for Prader-Willi syndrome

This project will develop a novel approach to enhance the function of the serotonin 2C receptor. Because this receptor system is important in regulating hunger and satiety with particular relevance to PWS, the small molecules developed may offer a new therapeutic approach.

Derivation of live Prader-Willi syndrome neurons from induced pluripotent stem (iPS) cells

Pluripotent stem cells are capable of making a variety of cell types in a dish. Dr. Lalande will use skin cells from those with PWS to make iPS cells. The cells will be an invaluable resource for the PWS research community, as they will allow researchers to study live PWS neurons.

MCH neurons in animal models of Prader-Willi syndrome

Dr. Gao has been studying changes in brain circuits in mouse models of PWS. In year 2 of FPWR support, he will examine the MCH neurons, which are key regulators of appetite and satiety.

Plasma oxytocin and other appetite-regulating hormones in Prader-Willi syndrome before and after treatment with intranasal oxytocin

Oxytocin is a neuropeptide that plays an important role in anxiety, trust, and appetite suppression. Dr. Einfeld will perform a clinical study to evaluate if oxytocin improves behavior and cognition in children with PWS. FPWR will support the accompanying laboratory studies to determine how a variet...

Hypocretin/orexin deficiency in Prader-Willi syndrome animal models

Dr. Gao is a neurobiologist with expertise on the orexin system, which regulates sleep/wake state, appetite, and reward circuitry. He will determine how this system is disrupted in mouse models of Prader-Willi syndrome.

Exenatide: A potential treatment for hyperphagia and obesity in persons with Prader-Willi syndrome

Identification of substances that substitute for the loss of snoRNAs from the Prader-Willi critical region

PWS is believed to be caused by loss of "snoRNA" genes on chromosome 15. Dr. Stamm's group has worked to characterize the function of snoRNAs. Here, he will collaborate with investigators at UCLA and perform high throughput screening to identify compounds that will substitute for snoRNA function, a ...

Role of the HBII-85 snoRNA cluster in the pathogenesis of PWS

Dr. Beaudet's group was the first to pinpoint the snoRNA cluster on chromosome 15 as the critical region missing in patients with PWS. He will extend his studies to identify how inactivation of this region leads to the characteristics associated with PWS.

An improved mouse model of Prader-Willi syndrome (year 2)

Year 2 of funding will allow characterization of Dr. Resnick’s “conditional” mouse model of PWS

R Loop structures maintain epigenetic imprints at the Prader-Willi Imprinting Center (year 2)

In year 2 of funding, Dr. Chedin will extend his studies on the role of “R loops” in establishing and maintaining imprinting in the PWS critical region on chromosome 15.

The risk of early onset Alzheimer's disease in Prader-Willi syndrome

Dr Holland and colleagues will interview families and caregivers of adults with PWS who are over 40 to determine if those will PWS are at increased risk for developing AD.

R-Loop structures maintain epigenetic imprints at the Prader-Willi imprinting center

Dr. Chedin is examining the unusual DNA structure at the PWS critical region to understand how the paternal chromosome remains active while the maternal chromosome is silenced. His studies to better understand the mechanism of imprinting might lead to new treatment avenues for PWS.

Exploring the potential mitochondrial dysfunction in mouse models of Prader-Willi syndrome

There is some suggestion that individuals with PWS may have abnormalities in the function of mitochondria, the 'powerhouse' of the cell. Dr. Kimonis will use a variety of sophisticated methods to determine if the mitochondria are properly functioning in mouse models of PWS.

The effect of growth hormone replacement therapy on physical and behavioral sexual development in persons with PWS

Year 2 of Drs. Myers and Whitman’s study on adolescents and adults with PWS to determine how GH therapy changes maturation and development.

Behavioral treatment of obsessive-compulsive symptoms

Obsessive-compulsive (OC) symptoms can significantly impact quality of life for those with PWS. Although medications can be helpful, there is a risk of side effects. Behavioral treatment of OC symptoms can be very effective in the general population. Here, Dr. Storch will develop and test a treatmen...

An improved mouse model of Prader-Willi syndrome

Dr. Resnick's group will develop a mouse model that has a 'conditional knockout' of the PWS region. This new mouse may bypass the early failure to thrive stage, perhaps allowing them to develop the obesity common in PWS. The mouse will also be a highly useful resource for the PWS research community,...

Activation of the maternal allele at the PWS/AS domain (Year 2)

In year 2 of this project, Dr. Razin’s group will continue studies characterizing a protein that is involved in turning off the genes in the PWS region. They will determine if manipulation of this protein can cause the PWS-region genes to be reactivated.

Synaptology in Prader-Willi syndrome

Dr. Horvath has published fascinating studies on how ghrelin alters neuronal connections in mice. Here, he will investigate the effects of high levels of ghrelin on neuronal communication in PWS.

The role of the midbrain dopaminergic reward circuitry in ghrelin's effects on food intake and body weight

It remains unclear how, or even if, high levels of ghrelin in PWS drive food seeking behavior. Dr. Zigman, a new investigator in the Division of Hypothalamic Research at UTSW, will explore the effects of ghrelin on the dopamine-containing neurons in the midbrain, an area of the brain associated with...

Activation of the maternal allele at the PWS/AS domain as a potential therapeutic approach (year 1)

Dr. Razin’s group is studying a protein that is involved in turning off the genes in the PWS region. This project will further characterize that protein and explore whether altering expression of the protein can reactivate the genes in the PWS region.

Exploring the potential of using demethylation drugs to treat PWS

In PWS, the maternal chromosome is silenced by DNA methylation. Dr. Jiang will explore whether demethylating drugs, which are coming into use in cancer therapy, might be able to activate PWS-region genes. These studies will be done in cells from PWS individuals and in a mouse model of PWS.

PWS mouse model with deleted snoRNA cluster

This research will focus on understanding how the genetic changes that cause PWS disrupt normal brain and body function, resulting in the symptoms of the syndrome. The better we understand these underlying biological pathways, the better equipped we will be to develop treatments that address the roo...

The effect of growth hormone replacement therapy on physical and behavioral sexual development in persons with PWS

Growth hormone replacement therapy GHRT has many beneficial effects in PWS, and is now typically initiated in young children or infants. Drs. Myers and Whitman will study the effects of GHRT on adolescents and adults with PWS to determine how GH therapy changes sexual maturation and development.

The autonomic nervous system in necdin-null mice

Dr. Wevrick will extend her study on necdin, one of the proteins encoded in the PWS region, to determine how loss of the necdin gene affects the function of the autonomic nervous system.

Regulation of expression of Prader-Willi syndrome region genes in the hypothalamus by nutritional and hormonal signals

Dr. O'Rahilly is a leading scientist in the field of hunger regulation, obesity and energy balance. In this project, he will determine how nutritional and hormonal signals in the hypothalamus influence expression of PWS-region genes, and evaluate approaches to manipulate this interaction.

Evaluation of sensory processing in individuals with PWS

Dr. Miller, an expert on sensory processing disorder, will determine if children with PWS have difficulties in the regulation of sensory stimuli.

snoRNAs located in the PWS critical region regulate alternative splicing of pre-mRNAs

Dr. Stamm described how the genetic defect in PWS disrupts the serotonin 2C receptor, which may alter the serotonin system in the brain. This study follows up on that observation by examining other genes that may be altered due to the loss of chromosome 15 material.

The sympathetic and enteric nervous systems in necdin-null mice

Necdin is one of the genes on chromosome 15 that is not expressed in those with PWS. Dr. Wevrick has shown that necdin is important in directing the normal growth of neurons. Here she will study how loss of the necdin gene affects innervation of the gastrointestinal tract and the function of the aut...

Linking learning with neurodevelopmental functioning: Management strategies for children with Prader-Willi syndrome

Dr. Olley’s team works has adapted a neurodevelopmental model of learning to children with PWS to assess their strengths and needs. A model of learning specific to PWS will be linked to optimized learning strategies, providing practical tools to improve learning for people with PWS.

Endocrine and molecular basis for Prader-Willi syndrome

Dr. Nicholls is studying the endocrine and biochemical basis of PWS using a model system. His work demonstrates that abnormalities outside the hypothalamus also contribute to PWS characteristics.

PYY and PP: Potential targets for co-treatment against hyperphagia and obesity

Continuation of previous award, described below. This proposal used advanced technology to examine differences in expression of genes that are important in PWS. This award also fulfills FPWR’s goal of funding projects by new scientists to help establish themselves as PWS researchers.

The orexin system in Prader-Willi syndrome

Orexins, recently discovered neurotransmitters, are important in regulating wakefulness, appetite and energy balance. Dr. Randeva’s work examines orexin biology in PWS.

Understanding the action of ghrelin in the brain: Identification of novel targets for hyperghrelinemia (year 2)

The long-term goal of these studies is to understand integration of hunger signaling circuits and identify drugs that will regulate the action of ghrelin and control appetite in individuals who overproduce ghrelin, as in PWS.

Ghrelin and peptide YY levels and gene expression in Prader-Willi syndrome

This proposal used advanced technology to examine differences in expression of genes that are important in PWS. This award also fulfills FPWR’s goal of funding projects by new scientists to help establish themselves as PWS researchers.

PYY 3-36 and PP: Potential targets for co-treatment against hyperphagia and obesity

Using genetically engineered mouse models, these investigators studied how PYY3-36 and PP regulate appetite, and whether these hormones might offer a long-term approach to controlling hunger and increasing metabolic rate.

Role of PWCR1 snoRNAs in Prader-Willi Syndrome

This project supported the development of a new PWS mouse model through deletion of the PWS ‘critical region’ snoRNAs.