RT Journal Article
SR Electronic
T1 Antisense oligonucleotide therapy for <em>KCNT1</em> encephalopathy
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.11.12.379164
DO 10.1101/2020.11.12.379164
A1 Lisseth Estefania Burbano
A1 Melody Li
A1 Nikola Jancovski
A1 Paymaan Jafar-Nejad
A1 Kay Richards
A1 Alicia Sedo
A1 Armand Soriano
A1 Ben Rollo
A1 Linghan Jia
A1 Elena Gazina
A1 Sandra Piltz
A1 Fatwa Adikusuma
A1 Paul Q. Thomas
A1 Frank Rigo
A1 Christopher A. Reid
A1 Snezana Maljevic
A1 Steven Petrou
YR 2020
UL http://biorxiv.org/content/early/2020/11/14/2020.11.12.379164.abstract
AB 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 mutations 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. The homozygous p.P924L (L/L) mouse model recapitulates 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 provides a proof of concept for ASO-based gene silencing as a promising therapeutic approach in KCNT1-associated epilepsies.Competing Interest StatementThe authors have declared no competing interest.