Epilepsy treatments for patients with mechanistic target of rapamycin (mTOR) disorders, such as tuberous sclerosis complex (TSC) or focal cortical dysplasia type II (FCDII), are urgently needed. In these patients, the presence of focal cortical malformations is associated with the occurrence of lifelong epilepsy, leading to severe neurological comorbidities. Here, we show that the expression of the actin cross-linking protein filamin A (FLNA) is increased in resected cortical tissue that is responsible for seizures in patients with FCDII and in mice modeling TSC and FCDII with mutations in phosphoinositide 3-kinase (PI3K)-ras homolog enriched in brain (Rheb) pathway genes. Normalizing FLNA expression in these mice through genetic knockdown limited cell misplacement and neuronal dysmorphogenesis, two hallmarks of focal cortical malformations. In addition, Flna knockdown reduced seizure frequency independently of mTOR signaling. Treating mice with a small molecule targeting FLNA, PTI-125, before the onset of seizures alleviated neuronal abnormalities and reduced seizure frequency compared to vehicle-treated mice. In addition, the treatment was also effective when injected after seizure onset in juvenile and adult mice. These data suggest that targeting FLNA with either short hairpin RNAs or the small molecule PTI-125 might be effective in reducing seizures in patients with TSC and FCDII bearing mutations in PI3K-Rheb pathway genes.

中文翻译：

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Filamin A抑制作用会降低局灶性皮质畸形小鼠模型的癫痫发作活性。

对于具有雷帕霉素（mTOR）疾病机械靶标的患者，如结节性硬化症（TSC）或II型局灶性皮质发育异常（FCDII），急需进行癫痫治疗。在这些患者中，局灶性皮质畸形的存在与终生癫痫的发生有关，导致严重的神经系统合并症。在这里，我们表明肌动蛋白交联蛋白丝蛋白A（FLNA）的表达在切除的皮层组织中增加，该组织负责癫痫发作的FCDII患者和模型化TSC和FCDII的小鼠中磷酸肌醇3-激酶突变（PI3K ）-ras同源物，富含脑（Rheb）通路基因。通过基因敲除限制了细胞错位和神经元畸形的发生，这些小鼠的FLNA表达得以正常化，这是局灶性皮质畸形的两个标志。另外，Flna敲除降低了癫痫发作频率，独立于mTOR信号传导。与媒介物治疗的小鼠相比，在癫痫发作之前用靶向FLNA，PTI-125的小分子治疗小鼠可减轻神经元异常并降低癫痫发作频率。另外，当癫痫发作后在幼年和成年小鼠中注射时，该治疗也是有效的。这些数据表明，以短发夹RNA或小分子PTI-125靶向FLNA可能有效减少患有PI3K-Rheb途径基因突变的TSC和FCDII患者的癫痫发作。与赋形剂处理的小鼠相比，癫痫发作之前减轻神经元异常并降低癫痫发作频率。另外，当癫痫发作后在幼年和成年小鼠中注射时，该治疗也是有效的。这些数据表明，以短发夹RNA或小分子PTI-125靶向FLNA可能有效减少患有PI3K-Rheb途径基因突变的TSC和FCDII患者的癫痫发作。与赋形剂处理的小鼠相比，癫痫发作之前减轻神经元异常并降低癫痫发作频率。另外，当癫痫发作后在幼年和成年小鼠中注射时，该治疗也是有效的。这些数据表明，以短发夹RNA或小分子PTI-125靶向FLNA可能有效减少患有PI3K-Rheb途径基因突变的TSC和FCDII患者的癫痫发作。