SYNGAP antisense oligonucleotide as therapy for human cognitive disorders

Unmet Need:

Recent human genetic studies have suggested that mutations in the SYNGAP1 gene are linked to intellectual disability (ID), autism spectrum disorders (ASD), neurodevelopmental disorders, high rates of epilepsy, and schizophrenia. SYNGAP1 is a gene that encodes SynGAP, a GTPase-activating protein that is highly enriched in nerve cells in the brain. SynGAP is found at the junctions between nerve cells, allowing for cell-to-cell communications to take place. The SYNGAP1 gene has 3 distinct transcriptional start sites and can be alternatively spliced to generate 4 distinct C-terminal isoforms, designated as α1, α2, β, and γ. Key pathophysiological symptoms of ID and ASD patients have been recapitulated in SYNGAP1 heterozygous (+/-) knockout mice, which exhibit epileptic circuit activity, altered synaptic transmission, and severe working memory deficits. These data suggest that SYNGAP1 haplo-insufficiency is likely pathogenic in the ID/ASD-associated SYNGAP1 cases; however, the contribution of each SYNGAP isoform to pathogenic SYNGAP1 haplo-insufficiency remains unclear to date. This missing information is critical for the development of gene therapies combating deficits of pathogenic haplo-insufficiency.

Technology Overview:

Johns Hopkins researchers have examined which splice variants rescue cellular phenotypes in SYNGAP1 haplo-insufficiency in vitro, using rodent neuronal cultures. These experiments show that expression of full-length and certain isoforms of SYNGAP1 can rescue synaptic and neuronal deficits in disease model cells. This information will help with developing strategies for genetic replacement treatments of SYNGAP1 disorders. The researchers identified antisense oligo nucleotides (ASOs) that can increase the expression of certain isoforms or total SYNGAP1, thus potentially rescuing SYNGAP1 function. These ASOs are potential therapeutic agents for SYNGAP1 haplo-insufficiency seen in intellectual disability and neurodevelopmental disorders.

Stage of Development:

The inventors have characterized the key isoforms of SYNGAP1 sufficient for synaptic function rescue in disease model neurons. They have completed screening of ASOs that increase the expression of certain isoforms or total SYNGAP1.

Publications:

1. Issued Patent: US11618900B2 - Modulating SYNGAP
2. Pending Divisional Application: US20230374510A1 - Modulating syngap
3. 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
4. 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.