RASopathies Research Grants Awarded
2024: Sattar Khoshkhoo, MD, Brigham and Women’s Hospital, $58,222
An iPSC-based Platform for Characterization of Neuronal Circuit Dysfunction in RASopathies
Summary:
RASopathies are a group of genetic disorders that affect multiple body systems and are often linked to neurocognitive issues like learning disabilities, autism, and epilepsy. These conditions arise due to overactive Ras-MAPK signaling, which plays a crucial role in brain development and function. However, the specific effects of Ras-MAPK overactivation on brain circuits are not well understood. This project aims to use patient-derived stem cells to model RASopathies and investigate how abnormal signaling impacts brain cell communication. Moreover, by testing drugs that inhibit the Ras-MAPK pathway, this proposal will evaluate the feasibility of using Ras-MAPK inhibitors as a therapeutic strategy to restore normal brain activity in affected individuals. This research platform will also enable future drug discovery for rare genetic diseases that affect brain circuits.
Past Awardees
2023: Jonathan Payne, MD PhD, Murdoch Children’s Research Institute, $60,755
Social Outcomes in Adults with RASopathies: The SOAR Study
Summary:
Psychosocial difficulties and increased mental ill-health have been described in some RASopathies, however the literature lacks a systemic account of these difficulties, especially in adulthood. Understanding the nature, severity and impact of mental health and psychosocial adversity in adults with a RASopathy will be critical to inform clinical practice and to guide intervention strategies. The overall goal of the SOAR study is to take a holistic approach to evaluating a broad road range of psychosocial outcomes in adults with a RASopathy, including mental health, social integration, quality of life and daily living skills. We will also examine how these outcomes relate to demographic and personal variables such as employment, housing arrangements, family composition, and health status. SOAR will be a survey-based study and include over 300 adults with a RASopathy across Australia and the UK. By comprehensively characterizing the psychosocial outcomes in adults with RASopathies, this project will help shape clinical services and management of individuals with RASopathies.
2022: Jos M Draaisma, MD PhD, Radboud University Medical Center, $60,100
The central conducting lymphatic system in patients with the Rasopathies Noonan Syndrome and CardioFacioCutaneous Syndrome with and without lymphatic disease
Summary:
To get a better insight into the central lymphatic system in adult volunteers with Noonan Syndrome (NS) and CardioFacioCutaneous (CFC) Syndrome without clinical symptoms or signs of lymphatic disease compared to healthy adult volunteers without disease and NS and CFC patients with severe lymphatic disease. This to enable therapy with MEK-inhibitors or lymphovenous anastomosis. The Dutch Noonan Syndrome Foundation participates in this study.
2021: Fabrice Jaffré, PhD, Weill Cornell Medical College, $75,431
Discovery of new therapies for hypertrophic cardiomyopathy in RASopathies using an innovative hiPSC-based high throughput drug screening platform
Summary:
Children with RASopathies often present with severe cardiomyopathies and have a 22% mortality rate by the end of the first year of life. Currently, no specific treatment exists for RASopathy children with hypertrophic cardiomyopathy, therefore there is an urgent need to identify novel therapeutic strategies. The overall goal of this proposal is to uncover innovative therapeutic approaches using human induced pluripotent stem cell-derived cardiomyocytes as a RASopathy disease model and as innovative human 2D and 3D high-throughput drug screening platforms. Completion of this proposal will identify therapeutic molecules for RASopathy children with hypertrophic cardiomyopathy at an unparalleled speed.
2020: Vanessa Fear, BSc (Hons), PhD, The University of Western Australia, Telethon Kids Institute, $69,885
Understanding RASopathies to better inform diagnosis and treatment
Summary:
The RASopathies are a set of syndromes that include cardiofaciocutaneous (CFC) Syndrome, Noonan Syndrome, Noonan Syndrome with lentigines, and Costello Syndrome. The syndromes are characterised by overlapping disease phenotype and there is a need to distinguish the different RASopathies in order to facilitate accurate patient diagnosis and identify better treatments. In this study we compare changes in patient DNA (genetic variants) that are causative of CFC and Noonan Syndrome. Further, we investigate a potential disease causing patient genetic variant to determine if they have CFC or Noonan Syndrome. The study harnesses gene editing technology to introduce genetic variants into stem cells, which are then matured into nerve cells. The nerve cell maturation process is monitored to identify syndrome-specific changes to inform syndrome classification in the patient, and to provide a better understanding of both CFC and Noonan Syndrome.
