此类癫痫有望用基因治疗

新加坡国立大学永禄林医学院(NUS Medicine)的研究人员正在研究一种治疗癫痫患者的疗法。癫痫是一种神经系统疾病，由大脑异常活动引起的反复发作所定义。

Researchers from the Yong Loo Lin School of Medicine, National University of Singapore (NUS Medicine) are working on a therapy that holds potential in treating patients with epilepsy, a neurological disorder defined by recurring seizures due to abnormal brain activity.

这是一种罕见的遗传性癫痫，这种癫痫反复发作与人类大脑中KCNA2基因的突变有关。

This was a rare genetic form of epilepsy linked to a mutation in the KCNA2 gene in the human brain, which is associated with recurring seizures.

这个名为Gapmer反义寡核苷酸(ASO)的特殊治疗方法可以特异性靶向和分解有缺陷的核糖核酸(RNA)，同时保持正常基因功能的完整。

A specialized treatment called a Gapmer antisense oligonucleotide (ASO) is designed to specifically target and break down faulty ribonucleic acids (RNA) while keeping normal gene function intact.

使用这种RNA疗法导致KCNA2基因中编码的有问题的钾通道蛋白显著减少，这有助于恢复正常的钾流并减少与癫痫相关的过度神经元活动。

Using this RNA therapy led to a notable decrease in a problematic potassium channel protein encoded in the KCNA2 gene, which helped restore normal potassium flow and reduce excessive neuron activity linked to epilepsy.

癫痫与过度兴奋的神经元有关，钾有助于抑制兴奋性水平。

Epilepsy is associated with hyper-excitable neurons, and potassium helps dampen the excitability levels.

KCNA2编码的钾离子通道就像一扇门，控制着细胞表面钾离子的流动，当该基因发生突变时，这扇门就失效了，钾离子就不能释放出来控制神经元的活动，从而导致癫痫。

The potassium channel encoded by KCNA2 is like a door that controls the potassium ion flow on the surface of the cells-;when the gene is mutated, the door fails to work and potassium cannot be released to control neuron activity, which results in epilepsy.

这项研究是在体外细胞样本上进行的，发表在核酸治疗领域的顶级期刊《分子治疗学·核酸》上。

Published in Molecular Therapeutics Nucleic Acids, a top journal in the field of nucleic-acidbased therapeutics, the research study was conducted on in vitro cell samples.

这项研究工作始于2021年，当时一名婴儿的家人找到了该团队，该婴儿患有多次全身性癫痫发作，对多种药物和传统治疗有抗药性。

The research work began in 2021, when the team was approached by the family of an infant who suffered from multiple generalised seizures that were resistant to multiple medications and conventional treatments.

虽然这项研究工作还处于早期阶段，在进入临床试验之前，还需要在实验室模型中进行进一步的测试，但这项研究的显著结果带来了希望，即在未来10到20年内，这种疗法可以用于治疗由细胞离子通道异常引起的遗传性疾病——通道病(channelopathy)——引起的严重癫痫患者。

While the research work is in early stages and will need to undergo further testing in laboratory models before moving to clinical trials, the remarkable results from the research offer hope that the therapy can be delivered to patients suffering from severe epilepsy caused by channelopathies, genetic disorders caused by abnormalities in the ion channels of cells, within the next 10 to 20 years.

研究小组正在研究的新的Gapmer技术也可以适用于同一基因的其他突变或其他离子通道基因，为不同的KCNA2相关问题提供个性化治疗的可能性，可能为那些对标准药物无反应的罕见癫痫患者提供有希望的结果。

The new Gapmer technology being worked on by the research team could also be adapted to target other mutations in the same gene or other ion channel genes-;opening the possibility of creating personalised treatments for different KCNA2-related issues, potentially offering hopeful outcomes for patients with rare forms of epilepsy that are unresponsive to standard medications.

Journal reference:

Huang, H., et al. (2024). Targeting heterozygous dominant negative variant of KCNA2 using Gapmer antisense oligonucleotides (ASO) for the treatment of drug-resistant epilepsy. Molecular Therapy — Nucleic Acids. doi.org/10.1016/j.omtn.2024.102316.