Noe' Francesco, Nissinen Jari, Pitkänen Asla, Gobbi Marco, Sperk Gunther, During Matthew, Vezzani Annamaria
Department of Neuroscience, Mario Negri Institute for Pharmacological Research, Via Eritrea 62, 20157 Milano, Italy.
Peptides. 2007 Feb;28(2):377-83. doi: 10.1016/j.peptides.2006.07.025. Epub 2006 Dec 28.
Gene therapy represents an innovative and promising alternative for the treatment of epileptic patients who are resistant to conventional antiepileptic drugs. Among the various approaches for the application of gene therapy in the treatment of CNS disorders, recombinant viral vectors have been most widely used so far. Several gene targets could be used to correct the compromized balance between inhibitory and excitatory transmission in epilepsy. Transduction of neuropeptide genes such as galanin and neuropeptide Y (NPY) in specific brain areas in experimental models of seizures resulted in significant anticonvulsant effects. In particular, the long-lasting NPY over-expression obtained in the rat hippocampus using intracerebral application of recombinant adeno-associated viral (AAV) vectors reduced the generalization of seizures from their site of onset, delayed acquisition of fully kindled seizures and afforded neuroprotection. These results establish a proof-of-principle for the applicability of AAV-NPY vectors for the inhibition of seizures in epilepsy. Additional investigations are required to demonstrate a therapeutic role of gene therapy in chronic models of seizures and to address in more detail safety concerns and possible side-effects.
基因治疗为治疗对传统抗癫痫药物耐药的癫痫患者提供了一种创新且有前景的替代方法。在基因治疗应用于中枢神经系统疾病治疗的各种方法中，重组病毒载体是目前使用最为广泛的。有几个基因靶点可用于纠正癫痫中抑制性和兴奋性传递之间受损的平衡。在癫痫发作实验模型的特定脑区转导神经肽基因，如甘丙肽和神经肽Y（NPY），可产生显著的抗惊厥作用。特别是，通过脑内应用重组腺相关病毒（AAV）载体在大鼠海马体中实现的NPY长期过表达，减少了癫痫发作从起始部位的扩散，延迟了完全点燃性癫痫发作的获得，并提供了神经保护作用。这些结果为AAV-NPY载体在癫痫发作抑制中的适用性建立了原理验证。还需要进一步研究来证明基因治疗在慢性癫痫发作模型中的治疗作用，并更详细地解决安全问题和可能的副作用。
