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Scn8a Antisense Oligonucleotide Is Protective in Mouse Models of SCN8A
Encephalopathy and Dravet Syndrome.
Authors Lenk GM, Jafar-Nejad P, Hill SF, Huffman LD, Smolen CE, Wagnon JL, Petit H, Yu
W, Ziobro J, Bhatia K, Parent J, Giger RJ, Rigo F, Meisler MH
Submitted By Submitted Externally on 3/26/2020
Status Published
Journal Annals of neurology
Year 2020
Date Published 3/1/2020
Volume : Pages 87 : 339 - 346
PubMed Reference 31943325
Abstract SCN8A encephalopathy is a developmental and epileptic encephalopathy (DEE)
caused by de novo gain-of-function mutations of sodium channel Nav 1.6 that
result in neuronal hyperactivity. Affected individuals exhibit early onset
drug-resistant seizures, developmental delay, and cognitive impairment. This
study was carried out to determine whether reducing the abundance of the Scn8a
transcript with an antisense oligonucleotide (ASO) would delay seizure onset and
prolong survival in a mouse model of SCN8A encephalopathy., ASO treatment was
tested in a conditional mouse model with Cre-dependent expression of the
pathogenic patient SCN8A mutation p.Arg1872Trp (R1872W). This model exhibits
early onset of seizures, rapid progression, and 100% penetrance. An Scn1a +/-
haploinsufficient mouse model of Dravet syndrome was also treated. ASO was
administered by intracerebroventricular injection at postnatal day 2, followed
in some cases by stereotactic injection at postnatal day 30., We observed a
dose-dependent increase in length of survival from 15 to 65?days in the
Scn8a-R1872W/+ mice treated with ASO. Electroencephalographic recordings were
normal prior to seizure onset. Weight gain and activity in an open field were
unaffected, but treated mice were less active in a wheel running assay. A single
treatment with Scn8a ASO extended survival of Dravet syndrome mice from 3?weeks
to >5 months., Reduction of Scn8a transcript by 25 to 50% delayed seizure onset
and lethality in mouse models of SCN8A encephalopathy and Dravet syndrome.
Reduction of SCN8A transcript is a promising approach to treatment of
intractable childhood epilepsies. Ann Neurol 2020;87:339-346.


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