Efficacy and safety of AAV2 gene therapy in children with aromatic L-amino acid decarboxylase deficiency: an open-label, phase 1/2 trial
Efficacy and safety of AAV2 gene therapy in children with aromatic L-amino acid decarboxylase deficiency: an open-label, phase 1/2 trial
复制标题
DOI：
10.1016/s2352-4642(17)30125-6
复制
发表时间：
2017-12-01
影响因子：
36.4
通讯作者：
Hwu, Wuh-Liang
中科院分区：
文献类型：
--
作者：
Chien, Yin-Hsiu;Lee, Ni-Chung;Hwu, Wuh-Liang
背景芳香族L-氨基酸脱羧酶（AADC）缺乏症是一种遗传性疾病，可导致婴儿和儿童神经递质耗竭和严重的运动功能障碍。我们先前报道了同情使用腺相关病毒（AAV）载体含有人类AADC基因（AAV 2-hAADC）在4名儿童AADC缺乏症（4-6岁）。在这项研究中，我们的目的是建立这种treatment.Methods的有效性和安全性，我们做了一个开放标签，1/2期临床试验在国立台湾大学医院（台北，台湾）。我们纳入的患者有明确的诊断和AADC缺乏症的临床症状（张力减退，肌张力障碍和动眼危象），年龄大于24个月或颅骨适合立体定向手术，抗AAV 2抗体滴度低于1.0光密度。所有患者通过立体定向脑手术接受双侧壳内注射AAV 2-hAADC（总共1.81 × 10（11）vg）。主要疗效结果是皮博迪发育运动量表（第二版; PDMS-2）评分增加超过10分，基因治疗后12个月脑脊液中高香草酸（HVA）或5-羟基吲哚乙酸（5-HIAA）浓度增加。我们在基线和基因治疗后3、6、9和12个月对患者进行了评估，此后每6个月评估一次，持续一年;所有接受治疗的患者都被纳入分析。我们在AAV 2基因治疗后3-7天评估了手术并发症（脑脊液漏和脑出血），并在12个月的随访评估期间评估了不良事件。该研究注册于ClinicalTrials.gov，编号NCT 01395641。结果10例患者（中位年龄2.71岁，IQR 2.46-6.35）于2014年10月1日至2015年12月2日入组。所有患者均耐受手术和载体注射。1例患者在治疗后10个月的地方性暴发期间死于流感B脑炎;因此，该患者的分析中纳入了9个月的数据。所有患者均达到主要疗效终点：基因治疗后12个月，PDMS-2评分增加中位数62分（IQR 39-93; p=0.005）和HVA浓度的中位数为25 nmol/L（IQR 11-48; p=0.012）;然而，5-HIAA浓度无显著变化（中位数差异0，IQR 0-5; p=0.20）。总共报告了101起不良事件，最常见的是发热（16/101起事件[16%]）和口面运动障碍（10/101起事件[10%]）。6例患者发生了12起严重不良事件，包括1例死亡（由于B型流感感染导致的治疗无关脑炎）、1例危及生命的发热和10起导致住院的事件。短暂的基因治疗后运动障碍发生在所有患者，但解决与利培酮。在31例治疗相关的不良事件中，只有一例（患者1）严重，没有一例导致住院或死亡。解释我们的研究结果表明，AAV 2-hAADC的壳内注射耐受性良好，可能会改善AADC缺乏症儿童的运动发育。
Background Aromatic L-amino acid decarboxylase (AADC) deficiency is an inherited disease that causes depletion of neurotransmitters and severe motor dysfunction in infants and children. We previously reported compassionate use of an adeno-associated virus (AAV) vector containing the human AADC gene (AAV2-hAADC) in four children with AADC deficiency (aged 4-6 years). In this study, we aimed to establish the efficacy and safety of this treatment.Methods We did an open-label, phase 1/2 trial at the National Taiwan University Hospital (Taipei, Taiwan). We included patients who had a definitive diagnosis and clinical symptoms of AADC deficiency (hypotonia, dystonia, and oculogyric crisis), who were older than 24 months or had skull bones suitable for stereotactic surgery, and who had an anti-AAV2 antibody titre lower than 1.0 optical density. All patients received bilateral intraputaminal injections of AAV2-hAADC (1.81 x 10(11) vg in total) through stereotactic brain surgery. Primary efficacy outcomes were an increase in the Peabody Developmental Motor Scales (second edition; PDMS-2) score of greater than 10 points and an increase in homovanillic acid (HVA) or 5-hydroxyindoleacetic acid (5-HIAA) concentrations in the cerebrospinal fluid 12 months after gene therapy. We assessed patients at baseline and at 3, 6, 9, and 12 months after gene therapy, and every 6 months thereafter for one further year; all patients who received the treatment were included in the analysis. We assessed for surgical complications (cerebrospinal fluid leakage and intracerebral haemorrhage) at days 3-7 after AAV2 gene therapy, and we assessed adverse events during the follow-up evaluations for 12 months. This study is registered with ClinicalTrials.gov, number NCT01395641.Findings Ten patients (median age 2.71 years, IQR 2.46-6.35) were enrolled from Oct 1, 2014, to Dec 2, 2015. All patients tolerated the surgeries and vector injections. One patient died from influenza B encephalitis during an endemic outbreak 10 months after treatment; therefore, 9 months of data were included in the analyses for this patient. All patients met the primary efficacy endpoint: 12 months after gene therapy, PDMS-2 scores were increased by a median of 62 points (IQR 39-93; p=0.005) and HVA concentrations by a median of 25 nmol/L (IQR 11-48; p=0.012); however, there was no significant change in 5-HIAA concentrations (median difference 0, IQR 0-5; p=0.20). In total, 101 adverse events were reported, with the most common being pyrexia (16 [16%] of 101 events) and orofacial dyskinesia (ten [10%]). 12 serious adverse events occurred in six patients, including one death (treatment-unrelated encephalitis due to influenza B infection), one life-threatening pyrexia, and ten events that led to hospital admission. Transient post-gene therapy dyskinesia occurred in all patients but was resolved with risperidone. Of 31 treatment-related adverse events, only one (patient 1) was severe in intensity, and none led to hospital admission or death.Interpretation Our findings suggest that intraputaminal injection of AAV2-hAADC is well tolerated and might improve motor development in children with AADC deficiency.Funding AADC Research Fund at National Taiwan University Hospital and the National Research Programme for Biopharmaceuticals.