STM：基因治疗芳香族氨基酸脱羧酶缺乏症

芳香族氨基酸脱羧酶（AADC,aromatic L-amino acid decarboxylase）在神经递质多巴胺和血清素的合成中必不可少，缺乏这一基因的儿童发育迟缓，特别是运动机能发育迟缓。药物治疗对于一些症状仅有轻微效果，并没有改善儿童的死亡率。

台湾国立大学医学院和日本、美国的研究人员合作，将腺相关病毒载体连接的AADC基因转入到4个4——6岁的病人的大脑核区中。4个病人的运动机能都得到改善。在基因转入16个月后，一个病人能够站立。基因转入6——15月，另外三个病人能够被支撑的坐立。相关论文发表在Science Translational Medicine上。

基因导入之后，通过正电子发射断层摄影术检测发现6-[18F]氟多巴的含量增加，它是AADC的一种示踪物。脑脊液分析也发现多巴胺和血清素水平增加。

这项研究的主要缺陷在于，基因导入之后仍会出现短暂的运动障碍，即两个病人出现吞咽时的口面运动障碍。其中一个病人鼻饲进食3个月，另一病人则出现愈发频繁的窒息，而在基因导入10个月后窒息现象消失。

研究结果表明，基因治疗对于AADC缺乏的儿童是可行的，可以刺激这些儿童的运动机能。而其本身存在的一些缺陷，如腺相关病毒载体可诱导产生抗腺相关病毒的抗体，这样再次导入基因时将不得不更换别的血清型的病毒载体。在克服这些缺陷之后，相信基因治疗AADC基因缺失可成功应用于临床。

doi:10.1126/scitranslmed.3003640
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Gene Therapy for Aromatic l-Amino Acid Decarboxylase Deficiency

Wuh-Liang Hwu1,2,*, Shin-ichi Muramatsu3, Sheng-Hong Tseng4, Kai-Yuan Tzen5,6, Ni-Chung Lee1, Yin-Hsiu Chien1, Richard O. Snyder7,8,9, Barry J. Byrne7, Chun-Hwei Tai10 and Ruey-Meei Wu10

Aromatic l-amino acid decarboxylase (AADC) is required for the synthesis of the neurotransmitters dopamine and serotonin. Children with defects in the AADC gene show compromised development, particularly in motor function. Drug therapy has only marginal effects on some of the symptoms and does not change early childhood mortality. Here, we performed adeno-associated viral vector–mediated gene transfer of the human AADC gene bilaterally into the putamen of four patients 4 to 6 years of age. All of the patients showed improvements in motor performance: One patient was able to stand 16 months after gene transfer, and the other three patients achieved supported sitting 6 to 15 months after gene transfer. Choreic dyskinesia was observed in all patients, but this resolved after several months. Positron emission tomography revealed increased uptake by the putamen of 6-[18F]fluorodopa, a tracer for AADC. Cerebrospinal fluid analysis showed increased dopamine and serotonin levels after gene transfer. Thus, gene therapy targeting primary AADC deficiency is well tolerated and leads to improved motor function.