A Phase I Study of Aromatic L-Amino Acid Decarboxylase Gene Therapy for Parkinson's Disease
A Phase I Study of Aromatic L-Amino Acid Decarboxylase Gene Therapy for Parkinson's Disease
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DOI：
10.1038/mt.2010.135
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发表时间：
2010-09-01
影响因子：
12.4
通讯作者：
Nakano, Imaharu
中科院分区：
文献类型：
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作者：
Muramatsu, Shin-ichi;Fujimoto, Ken-ichi;Nakano, Imaharu
多巴胺合成酶基因转移到纹状体神经元导致帕金森病动物模型的行为恢复。我们评估了腺相关病毒（AAV）载体介导的芳香l-氨基酸脱羧酶（AADC）基因进入PD患者壳核的安全性、耐受性和潜在疗效。6名PD患者在基线和6个月时进行评估，使用多种测量方法，包括统一帕金森病评定量表（UPDRS）、运动状态日记和使用6-[F-18]氟-l-m-酪氨酸（FMT）的正电子发射断层扫描（PET） （AADC的示踪剂）。对三名患者左旋多巴的短期反应进行了测量。这个手术是可以接受的。术后6个月，基于UPDRS评分，停药状态下的运动功能平均改善了46%，对左旋多巴的短期反应没有明显变化。PET显示FMT活性增加56%，持续到96周。我们的研究结果为AADC基因治疗的安全性和有效性提供了IV级证据，值得在随机对照的2期环境中进一步评估。
Gene transfer of dopamine-synthesizing enzymes into the striatal neurons has led to behavioral recovery in animal models of Parkinson's disease (PD). We evaluated the safety, tolerability, and potential efficacy of adenoassociated virus (AAV) vector-mediated gene delivery of aromatic l-amino acid decarboxylase (AADC) into the putamen of PD patients. Six PD patients were evaluated at baseline and at 6 months, using multiple measures, including the Unified Parkinson's Disease Rating Scale (UPDRS), motor state diaries, and positron emission tomography (PET) with 6-[F-18] fluoro-l-m-tyrosine (FMT), a tracer for AADC. The short-duration response to levodopa was measured in three patients. The procedure was well tolerated. Six months after surgery, motor functions in the OFF-medication state improved an average of 46% based on the UPDRS scores, without apparent changes in the short-duration response to levodopa. PET revealed a 56% increase in FMT activity, which persisted up to 96 weeks. Our findings provide class IV evidence regarding the safety and efficacy of AADC gene therapy and warrant further evaluation in a randomized, controlled, phase 2 setting.