FPWR is pleased to announce that we have recently awarded 13 project awards totaling $1.963M to support research aimed at advancing our understanding of Prader-Willi syndrome (PWS) and developing much-needed treatments. PWS is a complex genetic disorder that affects an estimated 1 in 15,000 people worldwide, and is characterized by a range of physical, cognitive, and behavioral symptoms.
The 13 funded projects will focus on topics related to PWS, including the underlying biology of the condition, potential therapeutic targets, and novel treatment approaches. Through this investment, we hope to make significant progress toward improving the lives of individuals with PWS and their families.
“We are looking forward to funding these exciting new projects that span the drug discovery and development pathway, as these researchers are very motivated to advance our understanding and treatment of Prader-Willi and Schaaf-Yang syndromes” says Theresa Strong, PhD, Director of Research Programs”.
Dr. Theresa Strong provides an update on ongoing research activities, new outcomes from the FPWR grant program, and a brief description of each of our newly funded in the recorded presentation below.
FPWR PWS Research Grant Recipients, Spring 2023
- POSTDOCTORAL FELLOWSHIP TO INVESTIGATE THE MOLECULAR BIOLOGY OF MAGEL2 IN SCHAAF-YANG AND PRADER-WILLI SYNDROMES. Christian Schaaf, MD, PhD, University of Heidelberg ($370,980). The MAGEL2 gene is of critical importance in both Prader-Willi and Schaaf-Yang syndromes. Studies using cell and animal models are needed to better understand the normal function of this gene and how mutations or loss of the protein leads to SYS and PWS. This funding will support a postdoctoral fellow in Dr. Christian Schaaf’s lab for 3 years, focused entirely on investigating the molecular biology of MAGEL2 in both PWS and SYS.
- ROLE OF MICROBIAL METABOLITES IN REGULATING HYPOTHALAMIC PATHWAYS INVOLVED IN FEEDING BEHAVIOR. Carles Lerin, PhD, Fundació Sant Joan de Déu ($75,600). The probiotic supplement, BPL1, shows promise improving metabolism and behavior in people with PWS, but more work is needed to understand how this gut microbiome intervention can be optimized. This project aims to understand how probiotic supplementation improves metabolic and mental health in individuals with PWS by influencing brain circuits regulating energy balance. Learn more about this project >>
- INTEGRATION OF SERUM METABOLOME AND GUT MICROBIOME TO IDENTIFY HOST-MICROBE METABOLIC INTERACTIONS IN PWS. Andrea Haqq, MD, University of Alberta ($56,876). This project will explore how the gut microbiome influences metabolic health in PWS. Dr. Haqq is collaborating with one of the world’s leading metabolomics lab (Dr. David Wishart) to characterize ‘metabolite’ profiles in children and adolescents with PWS and explore the links between blood metabolites, the gut microbe, and metabolic health in PWS.
- APPLICATION OF ADVANCED NEUROIMAGING TECHNIQUES IN PRADER-WILLI SYNDROME. Stephanie Brown, The University of Cambridge ($150,068). This research will use state-of-the-art neuroimaging techniques to advance our understanding of the neurobiology of two of the most challenging and difficult to manage aspects of PWS: hyperphagia and psychosis. The investigators will determine if imaging can detect changes in hypothalamic function in relation to eating behavior in PWS as well as how brain structure and neurotransmitter metabolism are altered in those with PWS who experience mental illness.
- MCH NEURON DYSREGULATION IN THE PATHOPHYSIOLOGY OF PRADER-WILLI SYNDROME. Vetrivelan Ramalingam, PhD, Beth Israel Deaconess Medical Center ($86,400). 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 research team will express ‘neural activity indicators’ in MCH neurons and measure the changes in their activity across several sleep-wake cycles in PWS mice, with the ultimate goal of identifying new drug targets for normalizing sleep in PWS.
- MAPPING THE HYPOTHALAMIC FUNCTIONAL ARCHITECTURE UNDERLYING APPETITE CONTROL IN THE PWS BRAIN. Giles Yeo, PhD, The University of Cambridge ($161,947). Working with the Autism BrainNet, Dr. Yeo and his team will examine hypothalamic tissue samples from six individuals with PWS. The research team apply cutting edge molecular analysis to these precious samples and to map the architecture of the PWS hypothalamus, providing insight into the changes underlying appetite control. They will create a comprehensive hypothalamic single cell database and a preliminary spatial map of hypothalamic cells in PWS, which will guide neurobiology research in the field.
- DECIPHERING THE ROLE OF OLFACTION IN PRADER-WILLI SYNDROME. Sophie Steculorum, PhD, Max Planck Institute for Metabolism Research ($144,320). 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, the team will examine the role of olfaction in both patients with PWS and a mouse model of PWS, and will explore how one potential treatment, oxytocin, impacts the olfactory system.
- TARGETING SMCHD1 TO ADDRESS THE UNDERLYING CAUSE OF PWS (YEAR 2). Marnie Blewitt, PhD, Walter and Eliza Hall Institute of Medical Research ($161,999). One potential gene therapy approach for PWS and SYS involves inhibiting the SMCHD1 gene to activate the PWS-region genes. In the first year of this study, Dr. Blewitt quantified the level of PWS gene activation that occurs in a PWS mouse model when SMCHD1 is removed. In this second year of funding, Dr. Blewitt will assess the approach in PWS patient cells in the lab and study whether removing SMCHD1 in a mouse model of PWS/SYS improves the symptoms.
- EVALUATION OF CART AS A POTENTIAL THERAPEUTIC TARGET FOR PWS USING A RAT MODEL. Gina Yosten, PhD, St. Louis University School of Medicine ($162,000). The goal of this study is to evaluate whether the appetite-regulating hormone, CART, is a viable therapeutic target for the treatment of hyperphagia in PWS. Dr. Yosten will determine if injection of CART reduces appetite in an obese PWS rat model (Magel2-deficient rats); if injection of CART increases secretion of pituitary hormones; and how Magel2 deficiency affects the biological rhythm of CART in brain tissues.
- THE ROLE OF MICROGLIA IN PRADER-WILLI SYNDROME AND A HYPOTHALAMIC GENE THERAPY. Lei Cao, PhD, The Ohio State University ($161,990). Recently, Dr. Cao showed that brain-derived neurotrophic factor (BDNF) gene therapy improves metabolic and behavior deficits observed in a mouse model of PWS. Follow-up studies showed that the PWS mice had an inflammatory profile in their brains, with activation of the brain’s resident immune cells, microglia, and that BDNF gene therapy reversed the inflammation. This study will assess whether microglia structure, function, and genetic profiles are altered in the PWS mouse, and will determine whether removing the microglia can prevent PWS-related metabolic problems.
- USING FUNCTIONAL NEAR-INFRARED SPECTROSCOPY TO IDENTIFY BIOMARKERS OF SKIN PICKING BEHAVIOR IN PWS. Scott Hall, PhD, Stanford University ($162,000). In previous research, Dr. Hall has found that altered internal bodily cues (interoceptive processes), such as pain, itch, and sensual touch, may be involved in skin picking behavior in PWS. Here, he will employ a sophisticated brain imaging method called functional near-infrared spectroscopy (fNIRS), which allows brain activity to be measured under more naturalistic settings, to examine which regions of the brain are activated before, during, and after the occurrence of skin picking behavior.
- NONINVASIVE NEUROMODULATION OF A NOVEL CEREBELLAR SATIETY CIRCUIT IN PWS. Laura Holsen, PhD, Brigham and Women’s Hospital ($161,819). Dr. Holsen and her collaborators recently identified a new brain pathway, the cerebellum-ventral striatum circuit, important in regulating appetite and satiation (feelings of fullness). This study will test whether safe, non-invasive modulation of this circuit, using a technique called transcranial magnetic stimulation (TMS), can impact the function of this circuit and reduce food intake in individuals with PWS.
- DETERMINING BELORANIB'S MECHANISM OF ACTION TO INFORM NOVEL DRUG TARGETS FOR PRADER-WILLI SYNDROME. Sarah Mitchell, PhD, Princeton University ($108,000). This team has been investigating how beloranib, a drug that effectively reduced hyperphagia and induced weight loss in individuals with PWS, worked. By defining downstream effectors of beloranib’s hyperphagia-reducing action, they hope to identify a safe and effective drug to treat hyperphagia in PWS.
