外显子
移植
前脑
细胞生物学
神经科学
生物
体内
HEK 293细胞
诱导多能干细胞
体外
突变
医学
遗传学
细胞培养
内科学
胚胎干细胞
中枢神经系统
基因
作者
X. Chen,Fikri Birey,Min-Yin Li,Omer Revah,Rebecca J. Levy,Mayuri Vijay Thete,Noah Reis,Konstantin Kaganovsky,Massimo M. Onesto,Noriaki Sakai,Zuzana Hudáčová,Jin Hao,Xiang-Ling Meng,Seiji Nishino,John R. Huguenard,Sergiu P. Pașca
出处
期刊:Nature
[Springer Nature]
日期:2024-04-24
卷期号:628 (8009): 818-825
标识
DOI:10.1038/s41586-024-07310-6
摘要
Abstract 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.
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