The Board of Directors has unanimously approved the funding of two research grants totaling $100,000 from the Hope Fund for 2024. Both projects have strong scientific merit and show promise into future Rett research. The Hope Fund was established in 2014 and, by the generosity of our community, has funded over $930,000 in Canadian research to date. O.R.S.A.’s Research Advisory Committee received and evaluated grant applications, comprised of impartial and prominent neurologists, geneticists and scientists from across Canada. O.R.S.A. would like to thank all those who applied for this opportunity. We are pleased to award funding to Dr. Wright to support research titled: “Investigating CtIP as a Genetic Modifier in Rett Syndrome” and Dr. Rossignol and Dr. LeRoux, to continue supporting their research funded by the Hope Fund in 2023 titled: Electrophysiological non-invasive biomarkers in Rett Syndrome evaluation.

Investigating CtIP as a Genetic Modifier in Rett Syndrome

Lay Summary:

Rett syndrome (RTT) is a severe neurological disorder predominantly caused by genetic mutations in the MECP2 gene. The disorder almost exclusively affects females, presents in childhood, and limited effective treatments exist. Since the disease can range in severity and age of onset, there is an active search in the research community for genes that may help explain these differences. These genetic modifier studies are essential since they can uncover new drug targets, leading to new treatments. Recent evidence from animal studies of RTT has suggested that the pathways that repair our genetic material (i.e., DNA) could be critical for modifying the clinical presentation of the disorder. The current investigation will study a key DNA repair gene in human RTT brain cells to help understand how these processes might be involved in the disease. We will take advantage of recent advances in cutting-edge technologies in genomics, gene editing and human stem cell biology to investigate DNA repair in disease-relevant cells. Findings from these investigations will provide crucial insights into disease processes in RTT and provide a platform to identify and study additional RTT modifiers. Further, such research can identify new avenues for future therapeutic interventions in RTT and other neurodevelopmental disorders.

Dr. Galen Wright, PhD

Wright Lab Neurogenomics Research

Dr. Galen Wright is an Assistant Professor and Tier 2 Canada Research Chair in Neurogenomics in the Department of Pharmacology and Therapeutics at the University of Manitoba. He is also a principal investigator in the PrairieNeuro Research Centre at the Kleysen Institute for Advanced Medicine and a research scientist at the Children’s Hospital Foundation of Manitoba. His research interests lie in the fields of precision medicine, neuroscience, and DNA repair. He completed his Ph.D. in Genetics at Stellenbosch University in 2012 and then received additional training in computational biology at the South African National Bioinformatics Institute. Dr. Wright moved to Canada in 2014 to start a postdoctoral fellowship at the University of British Columbia, where he performed precision medicine research in neurological disorders. In his independent research program, his team focuses on studying genetic modifiers of neurological disorders, with a key focus on Rett syndrome. They use a combination of large-scale bioinformatic analyses, combined with functional genomic experiments, to identify novel therapeutic targets to improve neurological disease management.

Wright Lab website https://galenwrightlab.com/

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Electrophysiological non-invasive biomarkers in Rett Syndrome evaluation

LAY SUMMARY 

This prospective single-center study, conducted at the CHU de Sainte Justine (Montreal, Quebec), aims to develop new non-invasive biomarkers of Rett syndrome progression in a pediatric cohort. Version date 11/22/2021 These biomarkers are based on functional and spectral connectivity including measurements of coherence and cortical integration in electroencephalogram, and mismatch negativity by auditory evoked potentials. Prospective data with repeated measurements one year apart will be collected in patients and age-matched controls, and disease evolution and level of severity (standardized scales as RSBQ and CGI) will be compared between both time points. These values will serve as a baseline for comparison in future therapeutic trials. Indeed, the first gene therapy in Rett Syndrome (REVEAL study, Taysha) is being launched at Ste-Justine, initially in adults, with a subsequent pediatric phase considered if the therapy is well tolerated in adults. Similar electrophysiological measurements will be conducted in the adult patients but an understanding of the evolution of such neural signatures in pediatric age groups is lacking. We thus propose to assemble a first large pediatric Rett syndrome cohort to document the natural evolution of these electrophysiological signatures over time, and to address how these biomarkers evolve with disease progression and therapies.

Dr. Elsa Rossignol

Dr. Elsa Rossignol is a pediatric neurologist at the CHU Sainte-Justine and an associate professor of clinics in the departments of Neurosciences and Pediatrics at the Université de Montréal. She is the recipient of the Canada Research Chair on the Neurobiology of epilepsy. Her research aims to clarify the molecular and cellular basis of pediatric epilepsies. Using Next Generation Sequencing in large cohorts of patients, her lab contributed to the identification of dozens of novel epilepsy genes. Furthermore, her lab uses multimodal approaches to study the network mechanisms by which mutations in these genes result in epilepsy and cognitive deficits, with a focus on their impact on network inhibition. Her recent work revealed the key role of cortical disinhibition in genetic generalized epilepsies with cognitive deficits, and the therapeutic benefits of re-establishing network inhibition on seizures, attention and cognitive flexibility. In addition, Dr. Rossignol is the Director of the Integrated Rett Syndrome Clinic at the CHU Sainte-Justine. Her clinical research on Rett syndrome aims to identify better biomarkers of disease progression, to optimize clinical scales to track disease state and to explore novel therapeutic options, including gene therapy. In particular, she is the lead PI for the REVEAL gene therapy trial for Rett syndrome (Taysha, NCT05606614). Altogether, as a clinician-scientist working in the field of rare diseases, Dr. Rossignol aims to advance care for children with genetic neurodevelopmental disorders including Rett syndrome.

Dr. Marie Le Roux

Dr. Marie Le Roux is a pediatric epileptology fellow at the CHU Sainte-Justine. She achieved her pediatric neurology residency in France, and a Master’s Degree in Neuroscience at Paris-Sorbonne University, France. She has particular interest in electrophysiology. She recently worked on high resolution EEG and source localisation in focal refractory epilepsies. Her main interest concerns electrophysiology in neurogenetic patients. She recently integrated the Rett Syndrome Clinic at the CHU Sainte-Justine. Her clinical research on Rett syndrome aims to identify non invasive biomarkers of disease progression through electrophysiology in order to help generate normative data in this population, which will serve as a baseline to compare post-therapy data in the context of future therapeutic interventions, including gene therapy.