Noe’ Francesco M., Sørensen Andreas T., Kokaia Merab, Vezzani Annamaria
Department of Neuroscience, Mario Negri Institute for Pharmacological Research, Milano, Italy
Experimental Epilepsy Group, Wallenberg Neuroscience Center, Lund University Hospital, Lund, Sweden
Available antiepileptic drugs, which mainly target neurotransmitter systems and ion channels, suppress seizures in approximately 70% of epilepsy patients. Surgical resection offers an alternative therapeutic option only for a minority of individuals with drug refractory seizures, thus there is urgent need of more effective therapies. An innovative therapeutic option is based on the overexpression in the epileptic focus of endogenous molecules with anticonvulsant properties, using a gene therapy approach. In particular, neuropeptide Y (NPY) represents a promising therapeutic gene candidate due to its anticonvulsant properties in several models of seizures. In the last decade, gene therapy approaches for overexpressing NPY used recombinant adeno-associated viral (rAAV) vectors because they are mostly neurotropic and mediate long term gene expression with apparent lack of toxicity. rAAV-mediated NPY overexpression in areas of seizure onset or generalization mediated anticonvulsant activity in various acute seizures models, retarded kindling progression, and reduced seizure frequency in a model of chronic temporal lobe epilepsy (TLE). Side effects were limited, thus suggesting that this therapeutic approach could be relatively safe. These results establish a proof-of-principle evidence of the anticonvulsant efficacy and safety profile of rAAV-NPY gene therapy approach, highligthing the possibility of using this alternative treatment strategy to control drug resistant seizures in focal onset epilepsy.
现有的抗癫痫药物主要作用于神经递质系统和离子通道，可使约70%的癫痫患者的癫痫发作得到抑制。手术切除仅为少数药物难治性癫痫患者提供了一种替代治疗选择，因此迫切需要更有效的治疗方法。一种创新的治疗方法是基于基因治疗，使具有抗惊厥特性的内源性分子在癫痫病灶中过表达。特别是，神经肽Y（NPY）因其在多种癫痫模型中的抗惊厥特性而成为一种有前景的治疗基因候选物。在过去十年中，用于NPY过表达的基因治疗方法使用重组腺相关病毒（rAAV）载体，因为它们大多具有嗜神经性，可介导长期基因表达且明显无毒性。rAAV介导的NPY在癫痫发作起始或扩散区域过表达，在各种急性癫痫模型中介导了抗惊厥活性，延缓了点燃进程，并降低了慢性颞叶癫痫（TLE）模型中的癫痫发作频率。副作用有限，因此表明这种治疗方法可能相对安全。这些结果为rAAV-NPY基因治疗方法的抗惊厥疗效和安全性提供了原理性证据，突出了使用这种替代治疗策略控制局灶性发作性癫痫中耐药性癫痫发作的可能性。
