SCN1A (transcriptional upregulation)

Class

AAV9 gene regulation therapy delivering a non-replicating episomal transgene encoding an engineered transcription factor (eTF_SCN1A) under a GABAergic-interneuron-selective (REGABA) promoter

Pathway

the engineered transcription factor binds upstream of the endogenous SCN1A gene to increase its expression, restoring NaV1.1 sodium channel density specifically in GABAergic inhibitory interneurons and thereby restoring inhibitory neuronal function lost in SCN1A-haploinsufficient Dravet syndrome

SCN1A is the gene encoding NaV1.1, a voltage-gated sodium channel that is concentrated in GABAergic interneurons—the brain's principal inhibitory neurons. These channels allow interneurons to generate the rapid electrical impulses needed to release the inhibitory neurotransmitter GABA, which restrains excitatory brain circuits. In Dravet syndrome, a severe childhood genetic epilepsy, one copy of SCN1A carries a loss-of-function mutation. This haploinsufficiency—roughly half the normal dose of functional channel—impairs interneuron firing, shifting brain circuits toward excess excitation and producing frequent, treatment-resistant seizures along with developmental impairment.

Rather than replacing the SCN1A gene outright, whose coding sequence is too large for standard viral delivery vehicles, this approach delivers an engineered transcription factor that binds near the native SCN1A gene and increases transcription from the remaining functional copy. Because the delivery vehicle's promoter is chosen to be active specifically in inhibitory interneurons, the resulting increase in channel expression is confined to the cell population where the deficit occurs. The broader rationale is that partial, cell-type-restricted restoration of channel dosage may be sufficient to normalize inhibitory tone in haploinsufficiency disorders generally, without the packaging and safety burdens of full gene replacement.