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Updated: Aug 27, 2025

Intrathecal Delivery of Antisense Oligonucleotides in the Rat Central Nervous System

Intrathecal Delivery of Antisense Oligonucleotides in the Rat Central Nervous System

Published on: October 29, 2019

Antisense oligonucleotide therapy for KCNT1 encephalopathy.

Lisseth Estefania Burbano¹, Melody Li¹, Nikola Jancovski¹

¹The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia.

|September 29, 2022

Summary

Gene silencing using antisense oligonucleotides (ASOs) effectively reduced seizures and improved outcomes in a mouse model of KCNT1-associated developmental and epileptic encephalopathy (DEE). This approach offers a promising therapeutic strategy for this severe epilepsy syndrome.

Keywords:

Epilepsy Gene therapy Genetics Mouse models Neuroscience

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Area of Science:

Neuroscience
Genetics
Pharmacology

Background:

Developmental and epileptic encephalopathies (DEEs) cause severe seizures and intellectual disability.
KCNT1 gene variants, particularly gain-of-function mutations, are a significant cause of EIMFS, a severe DEE.
Current treatments for KCNT1-associated DEE are limited, necessitating novel therapeutic strategies.

Purpose of the Study:

To investigate the efficacy of a gene-silencing antisense oligonucleotide (ASO) approach for KCNT1-associated DEE.
To evaluate ASO therapy in a newly developed mouse model of KCNT1-associated epilepsy.

Main Methods:

Generated a mouse model with the KCNT1 p.P924L pathogenic variant.
Administered a Kcnt1 gapmer ASO via intracerebroventricular injection to symptomatic homozygous mice.
Compared outcomes (seizure frequency, behavior, survival) with control ASO-treated mice.

Main Results:

Homozygous mice exhibited severe seizures and developmental compromise, mirroring human DEE.
Single ASO injection significantly reduced seizure frequency and improved behavioral abnormalities.
ASO treatment extended survival in treated mice compared to controls.
Neonatal ASO administration was well-tolerated and effective.

Conclusions:

Antisense oligonucleotide (ASO)-based gene silencing provides proof of concept as a potential precision therapy for KCNT1-associated DEE.
This approach demonstrates significant therapeutic potential for severe epilepsy syndromes caused by ion channel dysfunction.