Antisense oligonucleotide therapy for KCNT1 encephalopathy
Date
2022
Authors
Burbano, L.E.
Li, M.
Jancovski, N.
Jafar-Nejad, P.
Richards, K.
Sedo, A.
Soriano, A.
Rollo, B.
Jia, L.
Gazina, E.V.
Editors
Advisors
Journal Title
Journal ISSN
Volume Title
Type:
Journal article
Citation
JCI Insight, 2022; 7(23):1-20
Statement of Responsibility
Lisseth 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
Conference Name
Abstract
Developmental 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.
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Description
Published online: 22 November 2022
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© 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/.