Antisense oligonucleotide therapeutic approach for Timothy syndrome

Xiaoyu Chen, Fikri Birey, Min-Yin Li, Omer Revah, Rebecca Levy, Mayuri Vijay Thete, Noah Reis, Konstantin Kaganovsky, Massimo Onesto, Noriaki Sakai, Zuzana Hudacova, Jin Hao, Xiangling Meng, Seiji Nishino, John Huguenard and Sergiu P. Pașca ()
Additional contact information
Xiaoyu Chen: Stanford University
Fikri Birey: Stanford University
Min-Yin Li: Stanford University
Omer Revah: Stanford University
Rebecca Levy: Stanford University
Mayuri Vijay Thete: Stanford University
Noah Reis: Stanford University
Konstantin Kaganovsky: Stanford University
Massimo Onesto: Stanford University
Noriaki Sakai: Stanford University
Zuzana Hudacova: Stanford University
Jin Hao: Stanford University
Xiangling Meng: Stanford University
Seiji Nishino: Stanford University
John Huguenard: Stanford University
Sergiu P. Pașca: Stanford University

Nature, 2024, vol. 628, issue 8009, 818-825

Abstract: Abstract Timothy syndrome (TS) is a severe, multisystem disorder characterized by autism, epilepsy, long-QT syndrome and other neuropsychiatric conditions1. 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 8A2–6. 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 developed7, 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.

Date: 2024
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DOI: 10.1038/s41586-024-07310-6

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