The Ontario Rett Syndrome Association (O.R.S.A.) Board of Directors has unanimously approved the funding of two research grant totaling $150,000 from The Hope Fund for 2023. The Hope Fund has funded over $828,000 in Canadian research to date.
Grant applications were received and evaluated by O.R.S.A.’s Research Advisory Committee which is comprised of impartial and prominent neurologists, geneticists and scientists from across Canada. O.R.S.A. would like to thank all those individuals that applied for this grant.
The Hope Fund was established in 2014. The funds for this research grant were raised through donations and fundraising activities. O.R.S.A. continues to support research excellence and the development of a wide scope of Rett syndrome research across Canada.
We are pleased to award $100,000 to Dr. Ellis and Dr. Zani to support their research titled: Astrocyte-derived Extracellular Vesicles to Rescue Rett Syndrome Neurons.
Rett syndrome (RTT) astrocytes are less able to support maturation of synapses that interconnect neurons. Human astrocytes require the IGF1 receptor for optimal neuron support, and IGF1 is a promising RTT therapy. Astrocytes release small droplets called extracellular vesicles (EVs) containing messages in the form of genetic material called microRNA. EVs deliver the cargo to nearby neurons or into the bloodstream, and limited evidence suggests that healthy EVs rescue RTT neurons. Using ORSA and other funding, we produced astrocytes from healthy induced pluripotent stem cells (iPSC), isolated EVs and determined their microRNA cargo overlaps with those altered in RTT patient blood. We submitted a Stem Cell Network grant to test if healthy control EVs rescue RTT neuron activity.
To explore EV microRNAs as blood biomarkers for IGF1 drug treatment, it is essential to evaluate the EV cargo of RTT astrocytes. We are producing RTT patient astrocytes from stem cells and will determine which microRNAs have altered levels in RTT EVs compared to controls, and if IGF1 treatment normalizes the levels of microRNAs packaged into the RTT astrocyte EVs. The differential microRNAs corrected by IGF1 treatment will be candidate biomarkers, and their ability to rescue RTT neuron activity will be tested.
Hospital for Sick Children, Toronto Canada
Dr. Ellis completed his BSc at McGill University and his PhD at the University of Toronto with Dr. Alan Bernstein developing retrovirus vectors for gene targeting. His Post-Doctoral Fellowship studying the beta-globin Locus Control Region was mentored by Dr. Frank Grosveld in London UK. Dr. Ellis established his own research team at the Hospital for Sick Children in Toronto in 1994 with a focus on gene therapy for Sickle Cell Anemia. He subsequently developed MECP2 vectors for Rett syndrome, and vectors with reporter genes that mark specific cell types. For example, the EOS vectors express specifically in pluripotent stem cells and facilitate generation of patient induced Pluripotent Stem (iPS) cells. The Ellis lab currently uses these iPS cells in collaborative research teams to model Rett syndrome, Autism Spectrum Disorders and cardiomyopathies. New research directions concentrate on post-transcriptional regulation during human neurodevelopment, and the transfer of microRNA via extracellular vesicles. Dr. Ellis is Research Integrity Advisor at the Hospital for Sick Children.
Ellis Lab website http://lab.research.sickkids.ca/ellis/
Hospital for Sick Children, Toronto Canada
Dr. Zani is a Neonatal and Paediatric Surgeon at the Hospital for Sick Children in Toronto, Associate Professor at the Department of Surgery, University of Toronto, and Scientist in the Development and Stem Cell Biology Program at the Peter Gilgan Centre for Research and Learning, SickKids, Toronto, Canada. His clinical interests are congenital anomalies and minimally invasive surgery, and his research focuses on neonatal and pediatric conditions with high morbidity and mortality rates. The Zani lab studies extracellular vesicles (EVs), which are nanoparticles released by all cells for intercellular communication. As EVs carry cargo similar to their cells of origin, EVs can be pathogenesis mediators, biomarkers of disease severity, and therapeutic agents. Among various EV-based projects, the Zani lab has recently been investigating the signatures of EVs isolated from induced plurip
Zani Lab website: https://lab.research.sickkids.ca/zani/
We are also pleased to award $50,000 to Dr Marie LE ROUX and Dr. Elsa ROSSIGNOL, for RESEARCH PROJECT: Electrophysiological non-invasive biomarkers in Rett Syndrome evaluation.
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 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 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.
“We are thrilled to award the 2023 Hope Fund Grant to Drs, Ellis, Zani, Le Roux Rossignol,” said Sabrina Millson, President of the Ontario Rett Syndrome Association. “Their proposals are both innovative and promising, and we believe they have the potential to make a significant impact on the Rett Syndrome community.”
The Ontario Rett Syndrome Board