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Journal Article
Antisense oligonucleotide therapeutic approach for Timothy syndrome
2024
Overview
Timothy syndrome (TS) is a severe, multisystem disorder characterized by autism, epilepsy, long-QT syndrome and other neuropsychiatric conditions
1
. TS type 1 (TS1) is caused by a gain-of-function variant in the alternatively spliced and developmentally enriched
CACNA1C
exon 8A, as opposed to its counterpart exon 8. We previously uncovered several phenotypes in neurons derived from patients with TS1, including delayed channel inactivation, prolonged depolarization-induced calcium rise, impaired interneuron migration, activity-dependent dendrite retraction and an unanticipated persistent expression of exon 8A
2
–
6
. We reasoned that switching
CACNA1C
exon utilization from 8A to 8 would represent a potential therapeutic strategy. Here we developed antisense oligonucleotides (ASOs) to effectively decrease the inclusion of exon 8A in human cells both in vitro and, following transplantation, in vivo. We discovered that the ASO-mediated switch from exon 8A to 8 robustly rescued defects in patient-derived cortical organoids and migration in forebrain assembloids. Leveraging a transplantation platform previously developed
7
, we found that a single intrathecal ASO administration rescued calcium changes and in vivo dendrite retraction of patient neurons, suggesting that suppression of
CACNA1C
exon 8A expression is a potential treatment for TS1. Broadly, these experiments illustrate how a multilevel, in vivo and in vitro stem cell model-based approach can identify strategies to reverse disease-relevant neural pathophysiology.
Antisense oligonucleotides effectively decrease the inclusion of exon 8A of
CACNA1C
in human cells both in vitro and in rodents transplanted with human brain organoids, and a single intrathecal administration rescued both calcium changes and in vivo dendrite morphology of patient neurons.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 13/106
/ 14/19
/ Alternative Splicing - drug effects
/ Alternative Splicing - genetics
/ Animals
/ Autism
/ Autistic Disorder - drug therapy
/ Autistic Disorder - genetics
/ Calcium channels (voltage-gated)
/ Calcium Channels, L-Type - genetics
/ Calcium Channels, L-Type - metabolism
/ Cell Movement - drug effects
/ Female
/ Humanities and Social Sciences
/ Humans
/ Long QT Syndrome - drug therapy
/ Male
/ Mice
/ Mutation
/ Neurons
/ Oligonucleotides, Antisense - pharmacology
/ Oligonucleotides, Antisense - therapeutic use
/ Patients
/ Science
/ Toxicity
