The Foundation for Prader-Willi Research announces our second round of Research Awards in 2022, exceeding $1,800,000. Representing the largest single round of funding in FPWR history, we are excited to fund a robust group of 14 grants that encompass projects that will increase our foundational knowledge of PWS, explore new treatments for hyperphagia, and advance potential therapies into the clinic. FPWR is dedicated to supporting research that advances the understanding and treatment of Prader-Willi syndrome (PWS) and to that end, has awarded nearly $20,000,000 and funded 200+ research grants since 2003.
"The commitment of the PWS community is reflected in the breadth of work that FPWR is able to support in this round of grants, all of which ultimately moves us towards new therapies for our loved ones with PWS," says Theresa Strong, Director of Research Programs. "The pace of work has accelerated and we’re very excited about the promise of these projects."
Learn more about the projects recently funded through the FPWR Grants Program and the work FPWR is conducting to speed treatments for PWS in an upcoming webinar, Thursday, November 3rd. Theresa Strong, FPWR Director of Research Programs, will share details on each project, as well as outcomes from previously funded projects and new opportunities in PWS research. This webinar is expected to last 45 minutes, with additional time for questions and discussion. Click here to register.
Can't make it to the live webinar? Still register! A recording of the webinar will be shared with all registrants.
FPWR PWS Research Grant Recipients, Fall 2022
- ENGINEERING EPIGENOME EDITING TOOLS FOR SUSTAINED REACTIVATION OF MATERNAL PWS GENES (YEAR 2). Nahid Iglesias, Ph.D., Duke University. This proposal investigates the development of a potential epigenetic therapy for PWS. Year 1 of this project showed the researchers were able to reactivate several maternal silenced PWS genes. In year 2, they will determine the epigenetic requirements for a uniform and stable reactivation of the maternal PWS region in human cells using transient delivery of our epigenome editing tools.
- INVESTIGATION OF CEREBELLAR CONTROL OF STRIATAL DOPAMINE ACTIVITY AND FOOD INTAKE IN PWS. Albert Chen, PhD, Scintillon Institute. These researchers have demonstrated that activation of a distinct class of cerebellar neurons dramatically decreases food intake by reducing meal size without compensatory changes to metabolic rate. In this proposal, we will characterize this novel cerebellar satiation network and evaluate whether this network is disrupted in PWS mouse models and explore how manipulating dopamine activity can alleviate diet-induced obesity in PWS mouse models.
- PWS SMART-START – A RANDOMIZED CLINICAL TRIAL. Kasey Bedard, Ph.D., The Chicago School of Professional Psychology. This project aims to evaluate a parent training program (PWS Smart Start) for helping caregivers develop the skills they need to address challenging behavior and skill deficits common among children with Prader-Willi Syndrome. This project begins to lay the foundation for behavior analytic services for children with PWS, with the end goal of demonstrating the effectiveness of PWS Smart-Start specifically and, in general, the value of behavior analytic services that can be shared with key stakeholders for a variety of purposes, including promotion of insurance coverage for ABA.
- ASSESSING DGKK SIGNALING PATHWAY AS A SNORD116 TARGET IN THE PATHOGENESIS OF PWS. Yiying Zhang, Ph.D., Columbia University. This project will investigate the pathophysiological role of SNORD116, by testing the effects of Snord116 on a gene, DGKK, which we have implicated in PWS in studies of mouse and human brain. If SNORD116 is confirmed to interact with DGKK in brain regions relevant to PWS and influences DGKK expression levels, we will have identified a basic molecular mechanism that could account for some of the protean clinical manifestations of PWS. Implication of SNORD116 would rationalize efforts to activate the silent maternal copy of the gene; and implication of “downstream” genes like DGKK would suggest pharmacological targets for mitigation.
- DEFINING CELL-TYPE SPECIFIC SIGNATURES AND DYSREGULATED PATHWAYS FROM BLOOD AND BRAIN IN PWS (YEAR 2). David Godler, Ph.D., Murdoch Children’s Research Institute. In year 1 of this project, the researchers found increased UBE3A levels in white blood cells was linked to more severe autism features in non-deletion PWS. In year 2, we will examine if and how these findings may be specifically linked to genetic changes in the related brain immune cells (glial cells) which support the proper functioning of neurons in cortex and hypothalamus. Together these will: (i) define genetic pathways dysregulated in PWS blood and brain, and (ii) identify existing medications used for other conditions to target these pathways in future PWS clinical trials.
- IN THEIR OWN VOICES: DEVELOPING A SELF-REPORT MEASURE OF HYPERPHAGIA FOR INDIVIDUALS WITH PWS. Elisabeth Dykens, Ph.D., Vanderbilt University. Currently, hyperphagia is often assessed by proxy informants on the Hyperphagia Questionnaires. Leveraging insights from previous research -- and with input from a PWS Advisory Board, PWS focus groups, and our own experience in developing other PWS-specific measures—this project will develop a self-report measure of hyperphagic symptoms for individuals with PWS (MY-HQ). In doing so, we aim to circumvent their cognitive processing difficulties and tendencies to be secretive about their food-seeking.
- IMPAIRMENT OF NEURONAL MORPHOLOGY AND FUNCTION IN SNORD116 PRADER-WILLI SYNDROME MICE. Timothy Wells, Ph.D., Cardiff University. Data from the first year of this project show that in the postnatal period, mice that lack Snord116 have dramatic changes in neuronal morphology in both the cortex and hippocampus, brain regions that are essential for cognitive function. In the second phase of this project, we will characterize the electrical activity and functional circuitry of these neurons and conduct a detailed assessment of morphological impairment in adulthood. We will also determine the impact of these cortical and hippocampal deficits on cognitive flexibility in the context of reversal learning behavior.
- NON-CODING RNAS IN NEURONAL DIFFERENTIATION AND PWS. David Tollervey, University of Edinburgh. This project will create a wide picture of RNA-RNA and RNA-protein interactions during the development of brain cells, focusing on interactions of SNORD116, as well as SNORD115 and other ncRNAs synthesized from SNHG14. We will identify their direct interacting RNA and protein partners. Using mutant cell lines we will find specific changes in other RNAs and proteins resulting from their absence during neuronal differentiation. During the current project, we expect to make important discoveries about how brain-specific snoRNAs, particularly SNORD116, are regulated and function.
- TARGETING THE OREXIN SYSTEM TO TREAT PRADER-WILLI SYNDROME-ASSOCIATED HYPERPHAGIA. Richard O’Connor, Ph.D., Icahn School of Medicine at Mount Sinai. This project will use brain mapping techniques to investigate the extent to which a reduction of brain orexin (which regulates hunger and physical activity) in laboratory mice lacking Magel2 leads to an alteration to brain function, and test whether novel medications that can boost orexin signaling can reduce the obesity-related behaviors in these same laboratory mice. These experiments will greatly enhance our understanding of the changes in the brain that lead to extreme hunger and resulting behavioral problems in PWS, paving the way for further research.
- CELLULAR AND MOLECULAR BASIS FOR OBESITY IN PWS. Jeffrey Friedman, MD Ph.D., The Rockefeller University. This project will use a newly-developed tool to identify the specific nerve cells and genes that cause 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. These studies will lay a solid foundation for our understanding of the mechanisms underlying hyperphagia and obesity in PWS and will provide a means for identifying drugs that engage those drug targets to treat the disorder.
- ROLE OF FAT SENSING IN THE ALTERED FEEDING BEHAVIOR AND METABOLIC PHENOTYPE OF PRADER-WILLI SYNDROME. Juan Manuel Castellano, PhD, University of Córdoba. This research project will try to reverse the metabolic alterations and disrupted feeding behaviors observed before and after weaning in the Magel2-null mouse model of PWS by manipulating specific lipid sensors and mediators. If successful, the researchers will unveil the contribution of specific lipid signaling pathways to the metabolic alterations associated with PWS throughout development and lay the groundwork for designing tools to treat them in the future.
- shRNA/AAV9 GENE THERAPY FOR THE TREATMENT OF PRADER-WILLI SYNDROME. Ryan Butler, Ph.D., University of Texas Southwestern. 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.
- IMPACT OF BRIGHT LIGHT THERAPY ON ALL-CAUSE EXCESSIVE DAYTIME SLEEPINESS IN PRADER-WILLI SYNDROME. Deepan Singh, MD, Maimonides Medical Center. Individuals with PWS have disrupted circadian rhythm, which can impact mood, cognition, and metabolism, and recent FPWR-supported studies demonstrate that those with disrupted sleep are more likely to experience behavior challenges and mental health problems. Dr. Singh will be performing a clinical trial of bright light therapy in children (6-18 years old) with daytime sleepiness and will evaluate its effects on sleepiness, behavior and activity.
- ADMINISTRATION OF OLEOYLETHANOLAMIDE FOR HYPERPHAGIA IN PRADER-WILLI SYNDROME. Virginia Kimonis, University of California Irvine. This clinical trial will evaluate a supplement to address disruptions in the endocannabinoid system, which have been described in PWS, and will determine this supplement’s effect on hyperphagia.