image: Dr. Lacoste, uOBMRI, and OHRI
Credit: Dr. Lacoste, uOBMRI, OHRI, and SRF
Mill Valley, CA – September 12, 2024 – The SynGAP Research Fund 501(c)(3) announces a $128,888 grant to Dr. Baptiste Lacoste at the uOttawa Brain and Mind Research Institute (uOBMRI) and Ottawa Hospital Research Institute (OHRI). This grant supports Dr. Lacoste's pioneering research project aimed at exploring the role of vascular and metabolic dysfunction in SYNGAP1-Related Non-Syndromic Intellectual Disability (SYNGAP1-NSID), also known as SYNGAP1-Related Disorders (SRD).
With elevated energy demands and a limited capacity to store energy, the developing brain depends heavily on a continuous supply of oxygen and nutrients from the bloodstream. The process by which the brain regulates the delivery and use of these energy sources is known as metabolism. During brain development, the formation of vascular networks is well-orchestrated to ensure proper blood perfusion and growth of neural circuits. However, defects in the vascular system, particularly those occurring early in life due to genetic mutations like SYNGAP1, may lead to atypical brain maturation and contribute to the cognitive and neurological challenges associated with SRD.
Dr. Lacoste's research represents a significant paradigm shift by focusing on the non-neuronal and metabolic aspects of SRD, an area that has remained largely unexplored. His team hypothesizes that SYNGAP1 deficiency triggers major metabolic changes in the brain, resulting from non-neuronal defects. Using advanced technologies and mouse and cellular models, this research will determine the impact of SYNGAP1 deficiency on cerebrovascular maturation, investigate its effects on angiogenic and metabolic function, as well as quantify brain growth and behavior in mice with a vascular-specific SYNGAP1 deficiency. This groundbreaking work is expected to fill a critical gap in understanding SRD and pave the way for developing new therapies and diagnostics, which are desperately needed by patients and their families.
In addition to this grant, SRF has previously supported Dr. Lacoste's research with two startup grants of $10,000 and $15,000. These grants have been instrumental in laying the groundwork for the current study by helping Dr. Lacoste to acquire patient-derived pluripotent stem cells.
Why We Supported This Project
For families, the most urgent need is finding better treatments that can alleviate the challenges their children face every day. This research explores new areas of the disorder: how the brain's energy use and blood flow might be affecting symptoms, which has not been previously investigated for SRD. By uncovering these connections, this project could lead to more effective therapies and or diagnoses to make a real difference in the daily lives of patients and care partners, giving families hope for a brighter future. Today, there are no therapies specifically for SRD and it is difficult to overstate the burden living with this disease places on the patients, families, and caregivers.
Recent Publication
Dr. Baptiste Lacoste's recent publication, "A Vascular-Centric Approach to Autism Spectrum Disorders" lays the foundation for the proposed research into SYNGAP1-Related Disorders (SRD). This statement highlights how blood vessel dysfunction can play a significant role in neurodevelopmental disorders, an insight that Dr. Lacoste’s team will now apply to understanding SRD. By building on these concepts, the new project aims to uncover how similar vascular issues might contribute to the symptoms of SRD potentially leading to more effective treatments.
Praise for Dr. Lacoste
“We are thrilled to see Dr. Lacoste building his neurovascular research with iPSCs generated by SRF at our partners Transcripta Bio & SFARI. Leveraging these research-ready assets has allowed him to move quickly,” say Mike Graglia, Founder of SRF. He continues, “It’s important to note that Dr. Lacoste has been exceptionally collaborative, it is a pleasure to work with him.”
Per Dr. Ruth Slack (uOBMRI director) and Dr. Duncan Stewart (OHRI’s CEO), “Dr. Lacoste has established an internationally competitive research program that has made significant contributions to both scientific and academic domains. In addition, he has recruited and trained an exceptional research team that was the first worldwide to unravel the role of cerebrovascular abnormalities in autism spectrum disorders (ASD). This exceptional mentorship is remarkable by such a young investigator, who not only has the scientific knowledge and skill, but also the leadership ability to pursue exciting discoveries within this field.”
Family Donations Make Progress Possible
Every dollar that SRF grants was given or raised by families. This capital is precious. We are grateful to the families raising and caring for very sick children who find the energy to also raise money. In the case of this grant, the Canadian SRF community was able to raise funds via Overcome Syngap1.
Blane Dallen, of Beamsville, Ontario, has been a leader in fundraising. He has established an annual “Scramble for SYNGAP1” event to raise funds in Canada for SRF efforts. He says, “Seeing Canadian researchers focus on SYNGAP1 is exciting and motivating for the 40+ families diagnosed so far in Canada. We look forward to working with Dr. Lacoste.”
About Dr. Baptiste Lacoste
Research from Dr. Lacoste’s lab focuses on the formation, function, and maintenance of brain blood vessels. They are particularly interested in mechanisms underlying the impact of vascular dysfunction on neuronal development. As such, they investigate non-neuronal causes of neurodevelopmental disorders and autism, as well as the metabolic adaptations of the brain to vascular deficiencies. In 2020, the Lacoste lab became the first team worldwide to discover the role of cerebrovascular (endothelial) abnormalities in autism. The team published a ground-breaking study in the prestigious journal Nature Neuroscience, revealing that alterations in brain blood vessels contribute to autism. These findings opened a complete new research field which is currently in expansion worldwide. While this represented a major discovery in the autism research field, the question they now seek to tackle is whether such vascular abnormalities also exist in SYNGAP1-related intellectual disability. As most studies have focused on neuronal aspects of the disease, these new research perspectives represent a paradigm shift, and a first attempt to investigate the vascular underpinnings of SYNGAP1-related intellectual disability.
About the Ottawa Hospital Research Institute (OHRI) and the uOttawa Brain and Mind Research Institute (uOBMRI)
The Ottawa Hospital Research Institute (OHRI) is the research arm of The Ottawa Hospital – one of Canada’s largest learning and research hospitals. Research at OHRI spans more than a hundred different diseases, conditions, and specialties with an overall focus on translating discoveries and knowledge into better health.
Established in 2012, the uOttawa Brain and Mind Research Institute (uOBMRI) is a unique network of international leaders working together to discover new treatments for neurological disorders and advancing brain health research. The uOBMRI leads neurodiscovery through innovative research that transforms prevention and care for the health of individuals and society.
About SYNGAP1-Related Disorders (SRD)
SYNGAP1-Related Disorders (ICD-10 F78.A1; ICD-11 LD90.Y) is a rare genetic disorder caused by variants on the SYNGAP1 gene that reduce SynGAP protein levels. SRF has identified over 1,454 patients to date, and the number grows weekly. This protein acts as a regulator in the synapses (where neurons communicate with each other). When SynGAP protein levels are too low, we see an increase in excitability in the synapses making it difficult for neurons to communicate effectively. This leads to many neurological issues seen in SynGAP patients.
Symptoms of SYNGAP1 include primarily neurological issues including autism spectrum disorder (ASD), intellectual disability, epilepsy, hypotonia (low muscle tone), gross and fine motor delays, global developmental delay, and visual abnormalities such as strabismus (crossed eyes) as well as gastrointestinal challenges and disordered sleep.
About the SynGAP Research Fund (SRF)
The mission of the SynGAP Research Fund (SRF) is to improve the quality of life for SYNGAP1 patients through the research and development of treatments, therapies, and support systems.
SRF was founded in the US in 2018 as a 501(c)(3) US public charity, and families created sister organizations for SRF in the UK in 2020, in Europe (Netherlands) in 2022, and in Latin America (Colombia) in 2023.
Completely family-led, SRF is the largest non-government funder of SynGAP research having committed over $6 million in grants. The founders cover operational costs, ensuring donations fund science & patient-related programs. SRF’s grant program awards one or two-year grants to investigators, physician residents, and clinicians interested in studying SYNGAP1. SRF grants are intended to help researchers explore novel ideas and answer open questions related to the clinical aspects of and therapies for SRD.
For more on SRF, visit curesyngap1.org or follow @cureSYNGAP1 on LinkedIn, YouTube, Instagram, Facebook, TikTok, or X.
SRF is a member of FasterCures, COMBINEDbrain, Global Genes Foundation Alliance, Everylife Foundation Community Congress, Epilepsies Action Network, Personalized Medicine Coalition, Rare Epilepsy Network, Epilepsy Leadership Council, Alliance for Genetic Etiologies in Neurodevelopmental Disorders and Autism (AGENDA), California Action Link for Rare Diseases, American Brain Coalition, Genetic Alliance UK, Rare Disease UK, Syndromes Without a Name (SWAN UK), Jumpstart Program, Patient Worthy, Autism Brain Net, Innovation and Value Initiative, Rare Disease Diversity Coalition, Cambridge Rare Disease Network, Breaking Down Barriers, Rare-X, Mencap, IndoUSRare, and The World Orphan Drug Congress.
Additional Resources on Dr. Lacoste's Cerebrovascular Research and Neurodevelopmental Disorders
For additional context on Dr. Lacoste’s work and the impact of cerebrovascular research on neurodevelopmental disorders, view SRF’s related webinar and these papers.
Ouellette J, Crouch EE, Morel JL, Coelho-Santos V, Lacoste B. (2024) A Vascular-Centric Approach to Autism Spectrum Disorders. Neurosci Insights. 19:26331055241235921. https://journals.sagepub.com/doi/10.1177/26331055241235921
Kotchetkov P, Blakeley N, Lacoste B. (2023) Involvement of brain metabolism in neurodevelopmental disorders. Int Rev Neurobiol. 173:67-113. https://www.sciencedirect.com/science/article/pii/S0074774223000818?via%3Dihub
Ouellette J, Toussay X, Comin CH, Costa LDF, Ho M, Lacalle-Aurioles M, Freitas-Andrade M, Liu QY, Leclerc S, Pan Y, Liu Z, Thibodeau JF, Yin M, Carrier M, Morse CJ, Dyken PV, Bergin CJ, Baillet S, Kennedy CR, Tremblay MÈ, Benoit YD, Stanford WL, Burger D, Stewart DJ, Lacoste B. (2020) Vascular contributions to 16p11.2 deletion autism syndrome modeled in mice. Nat Neurosci. 23(9):1090-1101. https://www.nature.com/articles/s41593-020-0663-1