Finding treatments for neurological disorders is challenging due to a lack of human brain tissue and an inability to recapitulate disease phenotypes in animal models. This is especially true for neurodevelopmental disorders, such as Timothy syndrome. Writing in Nature, Pașca and colleagues develop a rescue strategy for Timothy syndrome using only in vitro stem cell models and in vivo transplantation of patient-derived cells.

Timothy syndrome type 1 is a severe neurodevelopmental disorder that is caused by a variant of exon 8A in the CACNA1C gene, which encodes a subunit of the voltage-gated calcium channel. Based on previous work showing that a persistent expression of exon 8A leads to abnormal channel function, the authors hypothesized that switching exon utilization from 8A to its counterpart exon 8 could be a therapeutic strategy. To explore this, they developed antisense oligonucleotides (ASOs) that modulate splicing to decrease the inclusion of exon 8A. ASO administration rescued delayed channel inactivation and depolarization-induced calcium elevation in patient-derived cortical organoids, as well as interneuron migration defects in forebrain assembloids. These effects were validated in vivo following ASO administration after transplanting human Timothy syndrome cells into the developing cortex of newborn rats.

由于缺乏人类脑组织并且无法在动物模型中重现疾病表型，寻找神经系统疾病的治疗方法具有挑战性。对于蒂莫西综合征等神经发育障碍尤其如此。帕斯卡和同事在《自然》杂志上发表文章，仅使用体外干细胞模型和患者来源细胞的体内移植，开发了一种蒂莫西综合征的救援策略。

1 型蒂莫西综合征是一种严重的神经发育障碍，由CACNA1C基因中的外显子 8A 变异引起，该基因编码电压门控钙通道的一个亚基。基于先前的研究表明外显子 8A 的持续表达会导致通道功能异常，作者假设将外显子利用从 8A 切换到其对应的外显子 8 可能是一种治疗策略。为了探索这一点，他们开发了反义寡核苷酸（ASO）来调节剪接以减少外显子 8A 的包含。 ASO 给药可挽救患者来源的皮质类器官中的延迟通道失活和去极化引起的钙升高，以及前脑组合体中的中间神经元迁移缺陷。将人类蒂莫西综合征细胞移植到新生大鼠发育中的皮层后，使用 ASO 后，这些效果在体内得到了验证。