Scn8a Antisense Oligonucleotide Is Protective in Mouse Models of SCN8A Encephalopathy and Dravet Syndrome

Abstract

Objective SCN8A encephalopathy is a developmental and epileptic encephalopathy (DEE) caused by de novo gain‐of‐function mutations of sodium channel Nav1.6 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. Methods 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. Results 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. Interpretation 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

Nucleic Acid–Based Therapeutics in Orphan Neurological Disorders: Recent Developments

“…Similar results were observed in a mouse with conditional Cre-dependent expression of a pathogenic mutation Scn8a-R1872W/+, a model of SCN8A encephalopathy. This gain-of-function mutation of SCN8A-containing sodium channel Nav 1.6 results in neuronal hyperactivity and seizures ( Lenk et al, 2020 ).…”

Understanding In Vivo Fate of Nucleic Acid and Gene Medicines for the Rational Design of Drugs

“…About duration, efficacy of stable ASOs are long-lasting (several months) [ 335 , 336 ]. Duration of LNP containing siRNA or mRNA is relatively short (several days to weeks) [ 337 , 338 ]; thus, a more frequent dosage than chemically modified stable ASOs is required for LNP.…”

Gene Therapy in Models of Severe Epilepsy due to Sodium Channelopathy

“…In a separate paper, Lenk et al 9 use synthetic oligonucleotides (antisense oligonucleotides [ASOs])—an RNA-based gene-directed therapy—to modify disease pathogenesis in an experimental mouse model of SCN8A encephalopathy. Antisense oligonucleotides are short oligonucleotides engineered to specifically bind to a unique target RNA sequence and manipulate the levels of messenger RNA (mRNA) transcripts that encode specific target proteins via degradation or block of protein translation.…”