Gene therapy improves motor and mental function of aromatic l-amino acid decarboxylase deficiency
Gene therapy improves motor and mental function of aromatic l-amino acid decarboxylase deficiency
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DOI：
10.1093/brain/awy331
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发表时间：
2019-02-01
期刊：
影响因子：
14.5
通讯作者：
Yamagata, Takanori
中科院分区：
文献类型：
--
作者：
Kojima, Karin;Nakajima, Takeshi;Yamagata, Takanori
在芳香族L - 氨基酸脱羧酶（AADC）缺乏症患者中，大脑中儿茶酚胺和血清素水平的降低会导致发育迟缓和运动障碍。中国台湾地区已报道了基因疗法对1至8岁病情严重程度相同的患者的有益效果。我们对包括不同严重程度的青少年患者在内的人群进行了一项开放标签的1/2期研究。共纳入6名患者：4名男性（年龄分别为4岁、10岁、15岁和19岁）和1名女性（12岁）为严重表型，不能自主运动或说话；还有1名女性（5岁）为中度表型，能在辅助下行走。患者通过双侧壳核内输注接受了总计2×10¹¹个携带DDC的腺相关病毒载体基因组。在基因治疗后长达2年的时间里，所有患者的运动功能都有显著改善。3名严重表型患者能够在辅助下站立，1名患者能够借助助行器行走，而中度表型患者能够跑步和骑自行车。这名中度表型患者的智力功能也有所改善，能够流利交谈并进行简单的算术运算。所有患者的肌张力障碍消失，动眼危象明显减少。患者出现了几个月的短暂性舞蹈样运动障碍，但未观察到由载体引起的不良事件。使用6 - [F - 18]氟 - L - 间 - 酪氨酸（一种AADC的特异性示踪剂）进行的正电子发射断层扫描显示，壳核大面积区域的摄取持续增加。在我们的研究中，年龄较大的患者（>8岁）也有改善，尽管治疗对年龄较小的患者更有效。我们患者的基因背景是异质的，一些疑似有残余酶活性的患者比中国台湾地区的患者改善情况更好。除了运动症状的缓解，中度表型患者的认知和语言功能也有所改善。通过基因转移恢复壳核中的多巴胺合成，为本研究中所有年龄、基因型和疾病严重程度的患者都带来了变革性的医疗益处，其中中度患者的改善最为显著。
In patients with aromatic l-amino acid decarboxylase (AADC) deficiency, a decrease in catecholamines and serotonin levels in the brain leads to developmental delay and movement disorders. The beneficial effects of gene therapy in patients from 1 to 8 years of age with homogeneous severity of disease have been reported from Taiwan. We conducted an open-label phase 1/2 study of population including adolescent patients with different degrees of severity. Six patients were enrolled: four males (ages 4, 10, 15 and 19 years) and one female (age 12 years) with a severe phenotype who were not capable of voluntary movement or speech, and one female (age 5 years) with a moderate phenotype who could walk with support. The patients received a total of 2 x 10(11) vector genomes of adeno-associated virus vector harbouring DDC via bilateral intraputaminal infusions. At up to 2 years after gene therapy, the motor function was remarkably improved in all patients. Three patients with the severe phenotype were able to stand with support, and one patient could walk with a walker, while the patient with the moderate phenotype could run and ride a bicycle. This moderate-phenotype patient also showed improvement in her mental function, being able to converse fluently and perform simple arithmetic. Dystonia disappeared and oculogyric crisis was markedly decreased in all patients. The patients exhibited transient choreic dyskinesia for a couple of months, but no adverse events caused by vector were observed. PET with 6-[F-18]fluoro-l-m-tyrosine, a specific tracer for AADC, showed a persistently increased uptake in the broad areas of the putamen. In our study, older patients (>8 years of age) also showed improvement, although treatment was more effective in younger patients. The genetic background of our patients was heterogeneous, and some patients suspected of having remnant enzyme activity showed better improvement than the Taiwanese patients. In addition to the alleviation of motor symptoms, the cognitive and verbal functions were improved in a patient with the moderate phenotype. The restoration of dopamine synthesis in the putamen via gene transfer provides transformative medical benefit across all patient ages, genotypes, and disease severities included in this study, with the most pronounced improvements noted in moderate patients.