帕金森病基因治疗的临床前和临床研究

Preclinical and Clinical Studies on Gene Therapy of Parkinson's Disease

帕金森病灵长类动物模型的两种临床前基因治疗策略主要是,向脑黑质纹状体系统导入多巴胺合成酶基因或神经营养因子基因,以增加纹状体多巴胺水平或增强黑质残存神经元的存活能力。临床实验研究是将腺相关病毒介导的谷氨酸脱羧酶基因导入丘脑底核,使兴奋性神经递质谷氨酸变为抑制性神经递质GABA,从而抑制丘脑底核的靶核团苍白球内侧核和黑质网状部活性过高状态,使丘脑皮层通路的过度抑制被解除而达到治疗帕金森病的目的。

Two main strategies have being tested in pre-clinical works on gene therapy in a nonhuman primate model of Parkinson＇s disease, including introduction of therapeutic genes such as dopamine-synthetic enzymes or neurothophic factors in vivo or ex vivo into the nigrostriatal system to augment the striatal level of dopamine or to promote the survival of the remaining nigral neuron. In clinical trials in humans with Parkinson＇s disease, glutamic acid decarboxylase gene mediated by adeno-associated virus was transduced into the subthalamic nucleus where synthesis of the inhibitory neurotransmitter GABA was catalyzod by the enzyme from the excitory glutamic acid, as a result of the inhibition of overactivity of its terminal regions （ the internal segment of the globus pallidus and the substantia nigra pars reticulata）, eventuaUy leading to marked attenuation of over-inhibitory thalamocortical circuit and generation of therapeutic benefit.