Unmet Need:
SYNGAP1-related Intellectual Disability (SRID, MRD5) is a severe neurodevelopmental disorder (NDD) characterized by encephalopathy, intellectual disability (ID), autism spectrum disorder (ASD), and epilepsy and accounts for 0.5-1% of all NDDs and ~1% of the ~200 million ID cases worldwide (SYNGAP Research Fund, 2020). Supportive management in the form of allied therapies and anti-epileptic treatment remains the standard of care for SYNGAP1 patients, as there is currently no disease-modifying treatment available. As a monogenic NDD, therapies that directly address the causative SYNGAP1 gene variant and/or protein expression are the ideal treatment option for SYNGAP1 haploinsufficiency. Advances in gene therapies and gene therapy delivery systems provide an opportunity to achieve a cure for SRID should challenges in cargo size restrictions, modifications, packaging, and delivery be overcome.
Technology Overview:
Through three rounds of screening, researchers at Johns Hopkins have developed a highly efficient AAV-mediated gene therapy for SRID. Recent discoveries by these researchers have uncovered SYNGAP1 minigenes that can rescue synaptic plasticity deficits in disease model neurons. By using these minigenes and optimizing the vector, the inventors can deliver functional SYNGAP1 isoforms to the mouse brain at levels exceeding endogenous expression. Included in the vector are safety mechanisms to provide regulated expression to mitigate potential risks of long-lasting gene therapy and provide highly controllable gene expression.
Stage of Development: Pre-clinical data available.
Publications:
1. Araki Y, Rajkovich KE, Gerber EE, Gamache TR, Johnson RC, Tran THN, Liu B, Zhu Q, Hong I, Kirkwood A, Huganir R. SynGAP regulates synaptic plasticity and cognition independently of its catalytic activity. Science. 2024 Mar;383(6686):eadk1291. doi: 10.1126/science.adk1291. Epub 2024 Mar 1. PMID: 38422154
2. Araki Y, Gerber EE, Rajkovich KE, Hong I, Johnson RC, Lee HK, Kirkwood A, Huganir RL. Mouse models of SYNGAP1-related intellectual disability. Proc Natl Acad Sci U S A. 2023 Sep 12;120(37):e2308891120. doi: 10.1073/pnas.2308891120. Epub 2023 Sep 5. PMID: 37669379
3. Araki Y, Hong I, Gamache TR, Ju S, Collado-Torres L, Shin JH, Huganir RL. SynGAP isoforms differentially regulate synaptic plasticity and dendritic development. Elife. 2020 Jun 24;9:e56273. doi: 10.7554/eLife.56273. PMID: 32579114; PMCID: PMC7314543.
4. Araki Y, Zeng M, Zhang M, Huganir RL. Rapid dispersion of SynGAP from synaptic spines triggers AMPA receptor insertion and spine enlargement during LTP. Neuron. 2015 Jan 7;85(1):173-189. doi: 10.1016/j.neuron.2014.12.023. PMID: 25569349
5. WO 2023/196841
