Table 1.

Pathogenic mechanisms in the genetic epilepsies and therapeutic approaches

Genetic mechanism	Examples of genes	Therapeutic approaches applied in preclinical models (reference)	NIH clinical trial study ID (approach)
Recessive (null)	CLN2	ASO targeting a splice variant, upregulation of CLN2 [86]
Haploinsufficiency	SCN1A, CHD2, SYNGAP1, DEPDC5	SCN1A-ASO targeting an NMD-inducing exon (TANGO) [14]	NCT04442295 (TANGO ASO)
Gain-of-function	SCN8A, KCNT1	RNAse H1–mediated knockdown of Scn8a [17] and Kcnt1 [18]
Dominant negative	SMC1A, STXBP1
Imprinted	UBE3A	ASO reducing the Ube3a-AS, increase paternal Ube3a expression [79]	NCT04259281 (UBE3A-AS targeting ASO)