mTOR抑制剂治疗结节性硬化症相关癫痫发作的研究进展

Research progress of mTOR inhibitors in the treatment of tuberous sclerosis complex-associated seizures

结节性硬化症相关癫痫发作因其特定的基因机制,通常对一般抗癫痫发作药物的反应不佳。结节性硬化症的主要致病通路为TSC1或TSC2基因异常逐步导致mTOR通路的过度激活。鉴于mTOR是一个较好的抗癫痫靶点,近十余年来,有关mTOR抑制剂的有效性和安全性的临床前研究和临床研究陆续进行,为现有mTOR抑制剂的使用提供了较为充分的证据。目前第一代mTOR抑制剂中的雷帕霉素及其衍生物依维莫司已进入临床应用。本文通过综述总结证据表明,虽然没有充分证据证实雷帕霉素和依维莫司对于结节性硬化症中的皮质结节具有明显逆转作用,但是有充分证据证实雷帕霉素和依维莫司能够减少结节性硬化症相关癫痫发作的频率,且多见轻中度不良事件。此外,雷帕霉素和依维莫司仍存在局限性,即少见的严重不良事件,以及停药后癫痫发作易复发等问题。目前研究中的一些新型mTOR抑制剂可能具有不劣于雷帕霉素和依维莫司的有效性和安全性。

Tuberous sclerosis complex-associated seizures often does not respond well to general antiepileptic drugs due to the specific genetic mechanisms.The main pathogenic pathway of tuberous sclerosis complex is the excessive activation of the mTOR pathway due to abnormalities of TSC1 or TSC2 genes.Given that mTOR is a better antiepileptic target,preclinical and clinical studies on the efficacy and safety of mTOR inhibitors have been conducted over the last decade or so,which provides adequate evidence for the use of existing mTOR inhibitors.Currently,Rapamycin and its derivative Everolimus,among the first generation of mTOR inhibitors,have been used in clinical practice.This review summarises the evidence that,although there is insufficient evidence to confirm that Rapamycin and Everolimus significantly reverse cortical nodules in tuberous sclerosis complex,there is sufficient evidence to confirm that Rapamycin and Everolimus reduce the frequency of tuberous sclerosis complex-associated seizures and that mild-moderate adverse events are more often seen.In addition,Rapamycin and Everolimus still have limitations such as rare serious adverse events and easily recurrent seizures after withdrawal.Some of the new mTOR inhibitors currently under investigation may have efficacy and safety profiles that are not inferior to those of Rapamycin and Everolimus.