antisense oligonucleotides targeting SynGAP1 regulatory RNAs

Antisense oligonucleotides (ASOs) targeting SynGAP1 regulatory RNAs (regRNAs) represent a therapeutic approach developed by CAMP4 Therapeutics to treat SYNGAP1-related disorders (also known as SYNGAP1-related non-syndromic intellectual disability or developmental and epileptic encephalopathy). SYNGAP1-related disorder is a rare, autosomal dominant neurodevelopmental condition caused by haploinsufficiency of the SYNGAP1 gene, which leads to a ~50% reduction in functional SynGAP protein. SynGAP is a critical Ras GTPase-activating protein located at the postsynaptic density of excitatory synapses, where it regulates synaptic plasticity, AMPA receptor trafficking, and neuronal excitability. CAMP4's lead development candidate under this program is CMP-002 (formerly CMP-SYNGAP-01), an intrathecally administered ASO designed to bind to a specific non-coding regulatory RNA (such as a natural antisense transcript, or NAT) associated with the SYNGAP1 gene locus. By targeting and disrupting this regRNA, CMP-002 relieves transcriptional repression, thereby upregulating transcription from the wild-type SYNGAP1 allele and restoring SynGAP protein levels. Preclinical studies in humanized mouse models and non-human primates have demonstrated that CMP-002 can restore SynGAP protein levels, improve cognitive and motor deficits, and reduce seizure phenotypes. CAMP4 received regulatory clearances (including from the UK MHRA, Australia's TGA, and Argentina's ANMAT) to initiate a global Phase 1/2 clinical trial of CMP-002 in patients with SYNGAP1-related disorder in late 2026.