Safety and tolerability of gene therapy with an adeno-associated virus (AAV) borne GAD gene for Parkinson's disease: an open label, phase I trial
Safety and tolerability of gene therapy with an adeno-associated virus (AAV) borne GAD gene for Parkinson's disease: an open label, phase I trial
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DOI：
10.1016/s0140-6736(07)60982-9
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发表时间：
2007-06-23
期刊：
影响因子：
168.9
通讯作者：
During, Matthew J.
中科院分区：
文献类型：
--
作者：
Kaplitt, Michael G.;Feigin, Andrew;During, Matthew J.
背景帕金森病患者多巴胺能神经元的丢失导致基底神经节回路的改变，如丘脑底核抑制性GABA能输入的减少。我们的目标是测量安全性;目的探讨腺相关病毒（AAV）介导的谷氨酸脱羧酶（GAD）基因在帕金森病（PD）患者中的安全性、耐受性和潜在疗效。方法对11例男性和1例女性PD患者进行单侧丘脑底核注射腺相关病毒载体（AAV-GAD）的开放性、安全性和耐受性试验（平均年龄58.2岁，SD = 5.7岁）。4名患者在纽约长老会医院接受了低剂量、4名中等剂量和4名高剂量AAV-GAD。纳入标准包括Hoehn和Yahr 3级或更高，运动波动与大量关闭时间，和年龄70岁或更小。患者在基线和1，3，6，12个月后在北岸医院进行临床评估。疗效指标包括统一帕金森!的疾病评定量表（ADRS），日常生活活动量表（ADL），神经心理学测试，和PET成像与F-18-氟脱氧葡萄糖。该试验在www.example.com注册处注册，编号NCT 00195143。结果所有入选的患者均接受了手术，没有脱落或失访患者。没有与基因治疗相关的不良事件。在基因治疗后3个月，运动神经功能评分显著改善（p = 0.0015），主要是在手术对侧的身体一侧，并持续长达12个月。PET扫描显示，在丘脑代谢，这是有限的治疗半球，和临床运动评分和脑代谢之间的相关性在辅助motorarea.Interpretation的AAV-GAD基因治疗丘脑底核是安全的，晚期帕金森氏病患者的耐受性良好，这表明，在体内基因治疗在成人大脑可能是安全的各种神经退行性疾病。
Background 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.Methods 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 F-18-fluorodeoxyglucose. The trial is registered with the ClinicalTrials.gov registry, number NCT00195143.Findings 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.Interpretation 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.