Anti-seizure gene therapy for focal cortical dysplasia.
Anti-seizure gene therapy for focal cortical dysplasia.
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DOI：
10.1093/brain/awad387
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发表时间：
2024-02-01
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局灶性皮质发育不良是一种常见的皮质发育畸形亚型，通常表现为一系列认知和行为异常以及耐药性癫痫。II型局灶性皮质发育不良通常由体细胞突变引起，导致哺乳动物雷帕霉素靶蛋白（mTOR）活动过度，是接受癫痫手术的儿童中最常见的病理。然而，手术切除并不总是导致癫痫发作的自由，往往是排除了接近雄辩的大脑区域。基因治疗是一种有前途的潜在替代治疗，可能适用于代表不可接受的手术风险的病例。在这里，我们评估了基因治疗的基础上过度表达的Kv1.1钾通道在小鼠模型额叶局灶性皮质发育不良。将工程化钾通道（EKC）转基因置于人启动子的控制下，所述人启动子使表达偏向于主要神经元（CAMK 2A），并包装在腺相关病毒载体（AAV 9）中。我们使用了一个建立局灶性皮质发育不良模型产生的额叶神经祖细胞子宫内电穿孔与组成型活性的人Ras同系物富集在脑（RHEB）质粒，激活mTOR复合物1。我们通过定量皮质电图和行为异常来表征该模型，无论是在自发性全身性癫痫发作的小鼠中还是在仅表现出发作间期放电的小鼠中。在发育不良区域中注射AAV 9-CAMK 2A-EKC导致癫痫发作频率的稳健降低（约64%）。尽管治疗具有强大的抗癫痫作用，但对额叶功能敏感的行为测试中的表现既没有改善也没有恶化。AAV 9-CAMK 2A-EKC对没有全身性癫痫发作的小鼠的发作间期放电或行为没有影响。AAV 9-CAMK 2A-EKC基因治疗是一种具有翻译潜力的治疗mTOR相关皮质发育畸形的癫痫表型的有前途的治疗方法。然而，认知和行为共病可能会抵制旨在降低电路兴奋性的干预。局灶性皮质发育不良（FCD）是导致难治性癫痫的皮质发育畸形的最常见病理学基础。Almacellas Barbanoj等人表明，基于Kv1.1钾通道过表达的基因疗法在减少II型FCD小鼠模型中的自发性癫痫发作方面非常有效。
Focal cortical dysplasias are a common subtype of malformation of cortical development, which frequently presents with a spectrum of cognitive and behavioural abnormalities as well as pharmacoresistant epilepsy. Focal cortical dysplasia type II is typically caused by somatic mutations resulting in mammalian target of rapamycin (mTOR) hyperactivity, and is the commonest pathology found in children undergoing epilepsy surgery. However, surgical resection does not always result in seizure freedom, and is often precluded by proximity to eloquent brain regions. Gene therapy is a promising potential alternative treatment and may be appropriate in cases that represent an unacceptable surgical risk. Here, we evaluated a gene therapy based on overexpression of the Kv1.1 potassium channel in a mouse model of frontal lobe focal cortical dysplasia. An engineered potassium channel (EKC) transgene was placed under control of a human promoter that biases expression towards principal neurons (CAMK2A) and packaged in an adeno-associated viral vector (AAV9). We used an established focal cortical dysplasia model generated by in utero electroporation of frontal lobe neural progenitors with a constitutively active human Ras homolog enriched in brain (RHEB) plasmid, an activator of mTOR complex 1. We characterized the model by quantifying electrocorticographic and behavioural abnormalities, both in mice developing spontaneous generalized seizures and in mice only exhibiting interictal discharges. Injection of AAV9-CAMK2A-EKC in the dysplastic region resulted in a robust decrease (∼64%) in the frequency of seizures. Despite the robust anti-epileptic effect of the treatment, there was neither an improvement nor a worsening of performance in behavioural tests sensitive to frontal lobe function. AAV9-CAMK2A-EKC had no effect on interictal discharges or behaviour in mice without generalized seizures. AAV9-CAMK2A-EKC gene therapy is a promising therapy with translational potential to treat the epileptic phenotype of mTOR-related malformations of cortical development. Cognitive and behavioural co-morbidities may, however, resist an intervention aimed at reducing circuit excitability. Focal cortical dysplasia (FCD) is the commonest pathology underlying malformations of cortical development resulting in intractable epilepsy. Almacellas Barbanoj et al. show that a gene therapy based on overexpression of the Kv1.1 potassium channel is highly effective in reducing spontaneous seizures in a mouse model of FCD type II.
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DOI：
10.1126/science.abq6656
发表时间：
2022-11-04
期刊：
Science (New York, N.Y.)
影响因子：
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作者：
Qiu Y;O'Neill N;Maffei B;Zourray C;Almacellas-Barbanoj A;Carpenter JC;Jones SP;Leite M;Turner TJ;Moreira FC;Snowball A;Shekh-Ahmad T;Magloire V;Barral S;Kurian MA;Walker MC;Schorge S;Kullmann DM;Lignani G
通讯作者：
Lignani G
影响因子：
14.5
作者：
Perucca, Piero;Dubeau, Francois;Gotman, Jean
通讯作者：
Gotman, Jean
影响因子：
9.8
作者：
Lim, Jae Seok;Gopalappa, Ramu;Lee, Jeong Ho
通讯作者：
Lee, Jeong Ho
粘虫头部转录组的感觉基因鉴定
影响因子：
4.6
作者：
Liu, Zhenxing;Wang, Xiaoyun;Zhu, Fen
通讯作者：
Zhu, Fen
异位 HCN4 表达驱动小鼠 mTOR 依赖性癫痫
影响因子：
17.1
作者：
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