Michael Courtney of Turku Bioscience Center receives grant for research on SYNGAP1 missense variants and drug repurposing from SynGAP Research Fund (SRF) dba Cure SYNGAP1

(Press-News.org) Mill Valley, CA – December 18, 2024 – The SynGAP Research Fund 501(c)(3) dba Cure SYNGAP1 announced a $108,867 grant to Dr. Michael Courtney and Dr. Li-Li Li at the Turku Bioscience Centre, University of Turku, Finland, to advance their research on SYNGAP1 missense variants. Their project seeks to better understand the functional impact of these mutations and explore drug repurposing as a potential therapeutic approach. 

Dr. Courtney’s team will use advanced phenotyping techniques to assess how SYNGAP1 missense variants impact the protein’s interaction with key neuronal components, such as PSD95, which is crucial for synaptic function. The project will also evaluate repurposed drugs like Nortriptyline and Tanganil for their ability to restore normal protein function. This comprehensive approach could lead to new therapeutic strategies for patients with SYNGAP1-Related Disorders (SRD).

About This Project Dr. Courtney states, “When the SYNGAP1 gene encodes a truncation, caused by a nonsense, frame-shift or other mutation, loss of SynGAP1 protein results in disease. But what happens when there is a missense mutation in SYNGAP1? Is the protein expressed, is it stable, does it still function in neurons? Ultimately, are we sure is it responsible for disease? There have been tremendous advances in predictability of the pathogenicity of missense, but experimental evidence is lacking.”

This project leverages a series of functional tests to analyze SYNGAP1 missense variants, focusing on those that are already classified as pathogenic or are of uncertain significance. Dr. Courtney’s team is identifying any abnormal properties in these variants to evaluate their potential responsiveness to pharmacological treatments. “This project applies a panel of functional assays to a series of missense variants either already considered pathogenic or with unknown or conflicting classification. Detected aberrant properties among missense variants can be used to evaluate pharmacological modulation,” he adds. The team will specifically test three drugs with repurposing potential, aiming to show that the methodology used here could be scaled to study additional variants in the future. “By investigating several variants and drugs in combination, we expect to demonstrate the future scalability of our assays.”

What is a ‘Missense Variant’? A missense variant is a single change in the DNA sequence that leads to a substitution of one amino acid for another in the SynGAP protein. This alteration can affect the protein’s function and, in some cases, lead to disorders. However, not all missense mutations are harmful; some may have minimal or no impact on how the protein works. In neurodevelopmental conditions like SRD, even small changes can significantly alter brain function, making it crucial to distinguish between benign and pathogenic missense variants.

Why We Supported This Project Missense variants, which alter only a single amino acid in the protein, are understudied in neurodevelopmental disorders generally caused by Loss of Function (LOF), such as SRD. Understanding the unique effects of each of these mutations is critical for three reasons:  first, to determine which missense variants cause SRD and of those, which will be amenable to emerging gene-expression therapies; second, to find new drug targets that will be amenable to missense and other variants; and third, to provide a more nuanced understanding of the biology of SRD for all patients. This project aims to build on previous efforts, including earlier SRF-funded work, and leverage high-throughput screening to assess drug repurposing opportunities. Watch a message from SRF CEO Mike Graglia on the importance of this research.

Past Work by Recipient Dr. Michael Courtney and his team at Turku Bioscience have made significant strides in the study of SynGAP protein variants, particularly with their previous work funded by both SRF and Leon & friends e.V. This earlier project focused on identifying structural and functional defects in SYNGAP1 missense variants. Their findings highlighted the potential risks of therapies that increase SynGAP protein levels, especially for patients with missense mutations, where an increase in dysfunctional protein could worsen the condition. This groundbreaking research laid the foundation for the current project, which will build on these methods to further characterize variant-specific deficits and explore drug repurposing as a therapeutic strategy. 

Dr. Courtney also collaborates with Dr. Postilla, also at Turku, on an in silico missense project also supported by SRF.  The SynGAP Missense Server is publicly available at https://syngapmissenseserver.utu.fi/.

Voices from the Frontlines of SYNGAP1 Research Aaron J. Harding, MS, SRF board member, explained, “SRF initiated the SYNGAP1 Missense Analysis, Research and Therapeutics project, aka SMART to support critical work such as Dr. Courtney’s.  The partnership between SRF and Leon and Friends seeks to give missense patients and their families hope that treatment options will be available to them. With twenty percent of missense  variants of uncertain significance (VUS) expected to be pathogenic we have to figure this out.  It would be a loss if a missense patient had a mutation that was null but they were excluded from precision therapies/trials because we did not understand the mutation.”

Family Donations Make Progress Possible “As the parent of a child with a SYNGAP1 missense mutation, I am grateful to Dr. Courtney and his team for researching this vastly understudied group of patients,” says Suzanne Jones, SRF board Chair and parent to a child with a SYNGAP1 missense mutation. “Ensuring that missense patients are included in potential treatment discussions is both commendable and necessary. These families comprise 12% of the diagnosed SYNGAP1 population, and they deserve to be included as we seek therapeutic possibilities. Thank you to SynGAP Research Fund for not leaving families like ours behind!”

About Dr. Michael Courtney and the Neuronal Signalling Laboratory Dr. Michael Courtney is a Senior Research Fellow at the Turku Bioscience Centre, University of Turku, Finland. He leads the Neuronal Signalling Laboratory, focusing on understanding cellular signaling pathways in neurons and their implications for neurodevelopmental and neurodegenerative disorders. His team employs advanced imaging techniques and functional assays to investigate protein interactions and signaling mechanisms, aiming to identify potential therapeutic targets for conditions like SYNGAP1-Related Disorders (SRD).

About Turku Bioscience Centre The Turku Bioscience Centre is a joint research and core facility of the University of Turku and Åbo Akademi University in Finland. Established in 1992, it provides state-of-the-art technology and expertise to support cutting-edge research in biosciences. The Centre offers services in areas such as genomics, proteomics, bioinformatics, screening, and cell imaging, facilitating both academic and commercially oriented research projects. By fostering interdisciplinary collaboration and innovation, Turku Bioscience Centre plays a pivotal role in advancing biomedical research and education.

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 1,497 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 SRF’s Seven Core Scientific Programs SynGAP Research Fund has established seven comprehensive programs to focus on understanding the disease, accelerating research, and preparing for clinical trials. Our commitment to funding strategic initiatives reflects our urgency to drive breakthroughs and find treatments. These include the following:

BTS – Basic and Translational Science Purpose – Drug Repurposing SMART – SYNGAP1 Missense Analysis, Research & Therapeutics SBOM – SYNGAP1 Biomarkers & Endpoints Facilitate – Research Tools and Reagents SRDC – SYNGAP1– Related Disorders Characterization ProMMiS: Prospective Multidisciplinary, Multisite Study for Clinical Excellence – Natural History Study at Multidisciplinary Clinics This grant falls into the SMART program. Studying panels of missense variant proteins may help identify effective treatments for specific SYNGAP1 gene missense variants, leading to more druggable targets for all, and a more nuanced view of SRD. SRF has funded over $600K in SMART grants.

About the SynGAP Research Fund (SRF) dba Cure SYNGAP1 The mission of the SynGAP Research Fund (SRF) dba Cure SYNGAP1 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.  There are sister organizations founded by local families in the UK in 2020, Europe (Netherlands) in 2022, as well as both Australia & Latin America (Colombia) in 2023. 

Completely family-led, SRF is a leading funder of SynGAP research having committed over $6.2 million in grants to date. 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.

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