Antisense oligonucleotide therapy for KCNT1 encephalopathy

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dc.contributor.authorBurbano, L.E.
dc.contributor.authorLi, M.
dc.contributor.authorJancovski, N.
dc.contributor.authorJafar-Nejad, P.
dc.contributor.authorRichards, K.
dc.contributor.authorSedo, A.
dc.contributor.authorSoriano, A.
dc.contributor.authorRollo, B.
dc.contributor.authorJia, L.
dc.contributor.authorGazina, E.V.
dc.contributor.authorPiltz, S.
dc.contributor.authorAdikusuma, F.
dc.contributor.authorThomas, P.Q.
dc.contributor.authorKopsidas, H.
dc.contributor.authorRigo, F.
dc.contributor.authorReid, C.A.
dc.contributor.authorMaljevic, S.
dc.contributor.authorPetrou, S.
dc.date.issued2022
dc.descriptionPublished online: 22 November 2022
dc.description.abstractDevelopmental and epileptic encephalopathies (DEE) are characterized by pharmacoresistant seizures with concomitant intellectual disability. Epilepsy of infancy with migrating focal seizures (EIMFS) is one of the most severe of these syndromes. De novo variants in ion channels, including gain-of-function variants in KCNT1, have been found to play a major role in the etiology of EIMFS. Here, we test a potential precision therapeutic approach in KCNT1-associated DEE using a gene silencing antisense oligonucleotide (ASO) approach. We generated a mouse model carrying the KCNT1 p.P924L pathogenic variant; only the homozygous animals presented with the frequent, debilitating seizures and developmental compromise that are seen in patients. After a single intracerebroventricular bolus injection of a Kcnt1 gapmer ASO in symptomatic mice at postnatal day 40, seizure frequency was significantly reduced, behavioral abnormalities improved, and overall survival was extended compared to mice treated with a control ASO (non-hybridizing sequence). ASO administration at neonatal age was also well-tolerated and effective in controlling seizures and extending the lifespan of treated animals. The data presented here provide proof of concept for ASO-based gene silencing as a promising therapeutic approach in KCNT1-associated epilepsies.
dc.description.statementofresponsibilityLisseth Estefania Burbano, Melody Li, Nikola Jancovski, Paymaan Jafar-Nejad, Kay Richards, Alicia Sedo, Armand Soriano, Ben Rollo, Linghan Jia, Elena V. Gazina, Sandra Piltz, Fatwa Adikusuma, Paul Q. Thomas, Helen Kopsidas, Frank Rigo, Christopher A. Reid, Snezana Maljevic, Steven Petrou
dc.identifier.citationJCI Insight, 2022; 7(23):1-20
dc.identifier.doi10.1172/jci.insight.146090
dc.identifier.issn2379-3708
dc.identifier.issn2379-3708
dc.identifier.orcidAdikusuma, F. [0000-0003-2163-0514]
dc.identifier.urihttps://hdl.handle.net/2440/136754
dc.language.isoen
dc.publisherAmerican Society for Clinical Investigation (ASCI)
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/10915693
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/GNT1005050
dc.rights© 2022, Burbano et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
dc.source.urihttps://doi.org/10.1172/jci.insight.146090
dc.subjectKCNT1; encephalopathy; epilepsy; ASO; mouse model
dc.titleAntisense oligonucleotide therapy for KCNT1 encephalopathy
dc.typeJournal article
pubs.publication-statusPublished

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