Kaplitt Michael G, Feigin Andrew, Tang Chengke, Fitzsimons Helen L, Mattis Paul, Lawlor Patricia A, Bland Ross J, Young Deborah, Strybing Kristin, Eidelberg David, During Matthew J
Department of Neurological Surgery, Weill Medical College of Cornell University, New York, NY, USA.
Lancet. 2007 Jun 23;369(9579):2097-105. doi: 10.1016/S0140-6736(07)60982-9.
Dopaminergic neuronal loss in Parkinson's disease leads to changes in the circuitry of the basal ganglia, such as decreased inhibitory GABAergic input to the subthalamic nucleus. We aimed to measure the safety, tolerability, and potential efficacy of transfer of glutamic acid decarboxylase (GAD) gene with adeno-associated virus (AAV) into the subthalamic nucleus of patients with Parkinson's disease.
We did an open label, safety and tolerability trial of unilateral subthalamic viral vector (AAV-GAD) injection in 11 men and 1 woman with Parkinson's disease (mean age 58.2, SD=5.7 years). Four patients received low-dose, four medium-dose, and four high-dose AAV-GAD at New York Presbyterian Hospital. Inclusion criteria consisted of Hoehn and Yahr stage 3 or greater, motor fluctuations with substantial off time, and age 70 years or less. Patients were assessed clinically both off and on medication at baseline and after 1, 3, 6, and 12 months at North Shore Hospital. Efficacy measures included the Unified Parkinson's Disease Rating Scale (UPDRS), scales of activities of daily living (ADL), neuropsychological testing, and PET imaging with 18F-fluorodeoxyglucose. The trial is registered with the ClinicalTrials.gov registry, number NCT00195143.
All patients who enrolled had surgery, and there were no dropouts or patients lost to follow-up. There were no adverse events related to gene therapy. Significant improvements in motor UPDRS scores (p=0.0015), predominantly on the side of the body that was contralateral to surgery, were seen 3 months after gene therapy and persisted up to 12 months. PET scans revealed a substantial reduction in thalamic metabolism that was restricted to the treated hemisphere, and a correlation between clinical motor scores and brain metabolism in the supplementary motor area.
AAV-GAD gene therapy of the subthalamic nucleus is safe and well tolerated by patients with advanced Parkinson's disease, suggesting that in-vivo gene therapy in the adult brain might be safe for various neurodegenerative diseases.
帕金森病中多巴胺能神经元的丧失会导致基底神经节回路的改变，如丘脑底核的抑制性γ-氨基丁酸能输入减少。我们旨在评估将腺相关病毒（AAV）携带的谷氨酸脱羧酶（GAD）基因转移至帕金森病患者丘脑底核的安全性、耐受性及潜在疗效。
我们对11名男性和1名女性帕金森病患者（平均年龄58.2岁，标准差=5.7岁）进行了一项开放标签的单侧丘脑底核病毒载体（AAV-GAD）注射安全性和耐受性试验。4名患者在纽约长老会医院接受低剂量AAV-GAD，4名接受中等剂量，4名接受高剂量。纳入标准包括Hoehn和Yahr分期为3期或更高、存在显著“关”期的运动波动且年龄在70岁及以下。患者在北岸医院于基线时以及1、3、6和12个月后进行了停药及服药状态下的临床评估。疗效指标包括统一帕金森病评定量表（UPDRS）、日常生活活动量表（ADL）、神经心理学测试以及18F-氟脱氧葡萄糖PET成像。该试验已在ClinicalTrials.gov注册，注册号为NCT00195143。
所有入组患者均接受了手术，无失访或退出试验者。未发生与基因治疗相关的不良事件。基因治疗3个月后，运动UPDRS评分显著改善（p=0.0015），主要在手术对侧身体，且持续至12个月。PET扫描显示丘脑代谢显著降低，且仅限于治疗侧半球，同时辅助运动区的临床运动评分与脑代谢之间存在相关性。
丘脑底核的AAV-GAD基因治疗对晚期帕金森病患者安全且耐受性良好，这表明成人大脑的体内基因治疗对于各种神经退行性疾病可能是安全可行的。
