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. Key findings from researchers at Hopkins have identified a critical c-terminal isoform of SYNGAP1 essential for its role in synaptic plasticity, α1. Increasing this isoform from the intact allele of SYNGAP1 may prove as a safe and efficient therapeutic strategy, but the mechanism of splicing is currently unknown.
Technology Overview:
Researchers at Johns Hopkins have characterized an essential SYNGAP1 splice isoform and found that increasing this α1 isoform can rescue synaptic plasticity deficits in disease model assays. The researchers have subsequently developed splice-switching antisense oligonucleotides (ASO) that increase this crucial isoform of SYNGAP1 and thereby rescuing SYNGAP function. This strategy is designed to be an effective therapeutic for diseases resulting from SYNGAP1 haploinsufficiency such as epilepsy, intellectual disability, and autism spectrum disorders.
Value Proposition:
· ASO increases the essential endogenous SYNGAP1 isoform to rescue function.
· Strategy can be adapted for majority of LoF mutations associated with SRID.
· Applicable to several genetic neurodevelopmental disorders including intellectual disability, autism, and epilepsy.
· Suite of accompanying tools to enable rapid screening of SYNGAP1 ASOs.
· Accelerate therapeutic development for SYNGAP1 gene-related disorders.
Stage of Development: Pre-clinical data available upon request
Publications:
1. 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.
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. PMID: 37669379
3. 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. PMID: 38422154.
4. WO 2023/196847
Related Technology: C15962
