Tardieu Marc, Zérah Michel, Husson Béatrice, de Bournonville Stéphanie, Deiva Kumaran, Adamsbaum Catherine, Vincent Fanny, Hocquemiller Michael, Broissand Christine, Furlan Valérie, Ballabio Andrea, Fraldi Alessandro, Crystal Ronald G, Baugnon Thomas, Roujeau Thomas, Heard Jean-Michel, Danos Olivier
1 Pediatric Neurology, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud , Le Kremlin Bucêtre 94275, France .
Hum Gene Ther. 2014 Jun;25(6):506-16. doi: 10.1089/hum.2013.238. Epub 2014 May 5.
Mucopolysaccharidosis type IIIA is a severe degenerative disease caused by an autosomal recessive defect of a gene encoding a lysosomal heparan-N-sulfamidase, the N-sulfoglycosamine sulfohydrolase (SGSH), the catalytic site of which is activated by a sulfatase-modifying factor (SUMF1). Four children (Patients 1-3, aged between 5.5 and 6 years; Patient 4 aged 2 years 8 months) received intracerebral injections of an adeno-associated viral vector serotype rh.10-SGSH-IRES-SUMF1 vector in a phase I/II clinical trial. All children were able to walk, but their cognitive abilities were abnormal and had declined (Patients 1-3). Patients 1-3 presented with brain atrophy. The therapeutic vector was delivered in a frameless stereotaxic device, at a dose of 7.2×10(11) viral genomes/patient simultaneously via 12 needles as deposits of 60 μl over a period of 2 hr. The vector was delivered bilaterally to the white matter anterior, medial, and posterior to the basal ganglia. Immunosuppressive treatment (mycophenolate mofetil and tacrolimus) was initiated 15 days before surgery and maintained for 8 weeks (mycophenolate mofetil) or throughout follow-up (tacrolimus, with progressive dose reduction) to prevent elimination of transduced cells. Safety data collected from inclusion, during the neurosurgery period and over the year of follow-up, showed good tolerance, absence of adverse events related to the injected product, no increase in the number of infectious events, and no biological sign of toxicity related to immunosuppressive drugs. Efficacy analysis was necessarily preliminary in this phase I/II trial on four children, in the absence of validated surrogate markers. Brain atrophy evaluated by magnetic resonance imaging seemed to be stable in Patients 1 and 3 but tended to increase in Patients 2 and 4. Neuropsychological evaluations suggested a possible although moderate improvement in behavior, attention, and sleep in Patients 1-3. The youngest patient was the most likely to display neurocognitive benefit.
ⅢA型黏多糖贮积症是一种严重的退行性疾病，由编码溶酶体乙酰肝素-N-硫酸酯酶（N-磺基葡糖胺硫酸酯酶，SGSH）的基因的常染色体隐性缺陷引起，该酶的催化位点由硫酸酯酶修饰因子（SUMF1）激活。在一项Ⅰ/Ⅱ期临床试验中，4名儿童（患者1-3，年龄在5.5至6岁之间；患者4，年龄为2岁8个月）接受了脑内注射重组腺相关病毒载体血清型rh.10-SGSH-IRES-SUMF1。所有儿童均能行走，但认知能力异常且已下降（患者1-3）。患者1-3出现脑萎缩。治疗性载体通过无框架立体定向装置给药，剂量为7.2×10¹¹个病毒基因组/患者，在2小时内通过12根针同时注射，每次注射60μl，双侧注射至基底神经节前、中、后的白质。在手术前15天开始免疫抑制治疗（霉酚酸酯和他克莫司），并维持8周（霉酚酸酯）或整个随访期（他克莫司，逐渐减量），以防止转导细胞被清除。从纳入研究开始、神经外科手术期间以及随访的一年中收集的安全性数据显示，耐受性良好，未出现与注射产品相关的不良事件，感染事件数量未增加，也没有与免疫抑制药物相关的毒性生物学迹象。在这项针对4名儿童的Ⅰ/Ⅱ期试验中，由于缺乏经过验证的替代指标，疗效分析必然是初步的。通过磁共振成像评估的脑萎缩在患者1和3中似乎稳定，但在患者2和4中呈增加趋势。神经心理学评估表明，患者1-3的行为、注意力和睡眠可能有适度改善。最年幼的患者最有可能表现出神经认知益处。
