AAV9-CNS2-V4.1-dCas9-VP64

AAV9-CNS2-V4.1-dCas9-VP64 is an experimental gene therapy construct developed by Regel Therapeutics for the treatment of SCN2A haploinsufficiency, a condition linked to autism spectrum disorder, developmental delay, and epilepsy. The therapy utilizes an adeno-associated virus serotype 9 (AAV9) vector to deliver a CRISPR activation (CRISPRa) system. This system consists of a dead Cas9 (dCas9) fused to the VP64 transcriptional activator, designed to upregulate the expression of the remaining functional SCN2A allele. To ensure neuron-specific activity and minimize off-target effects in peripheral tissues like the liver, the expression of the dCas9-VP64 payload is driven by a proprietary engineered regulatory element called CNS2-V4.1. Preclinical studies in mice have demonstrated that this construct achieves robust and widespread expression in the brain following systemic administration.