Paediatric Neurology Department, Université Paris Sud and Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Sud, Le Kremlin-Bicêtre, France.
Paediatric Neurosurgery Department, Université Paris Descartes and Assistance Publique-Hôpitaux de Paris, Hôpital Universitaire Necker, Paris, France.
Lancet Neurol. 2017 Sep;16(9):712-720. doi: 10.1016/S1474-4422(17)30169-2. Epub 2017 Jul 14.
Mucopolysaccharidosis type IIIB syndrome (also known as Sanfilippo type B syndrome) is a lysosomal storage disease resulting in progressive deterioration of cognitive acquisition after age 2-4 years. No treatment is available for the neurological manifestations of the disease. We sought to assess the safety and efficacy of a novel intracerebral gene therapy.
Local regulatory authorities in France allowed inclusion of up to four children in this phase 1/2 study. Treatment was 16 intraparenchymal deposits (four in the cerebellum) of a recombinant adenoassociated viral vector serotype 2/5 (rAAV2/5) encoding human α-N-acetylglucosaminidase (NAGLU) plus immunosuppressive therapy. We assessed tolerance, neurocognitive progression, brain growth, NAGLU enzymatic activity in CSF, and specific anti-NAGLU immune response for 30 months after surgery. This trial is registered with EudraCT, number 2012-000856-33, and the International Standard Clinical Trial Registry, number ISRCTN19853672.
Of seven eligible children, the four youngest, from France (n=2), Italy (n=1), and Greece (n=1), aged 20, 26, 30, and 53 months, were included between February, 2012, and February, 2014. 125 adverse events were recorded, of which 117 were treatment emergent and included six classified as severe, but no suspected unexpected serious adverse drug reactions were seen. Vector genomes were detected in blood for 2 days after surgery. Compared with the natural history of mucopolysaccharidosis type III syndromes, neurocognitive progression was improved in all patients, with the youngest patient having function close to that in healthy children. Decrease in developmental quotient was -11·0 points in patient one, -23·0 in patient two, -29·0 in patient three, and -17·0 in patient four, compared with -37·7 in the natural history of the disease. NAGLU activity was detected in lumbar CSF and was 15-20% of that in unaffected children. Circulating T lymphocytes that proliferated and produced tumour necrosis factor α upon ex-vivo exposure to NAGLU antigens were detectable at 1-12 months and 3-12 months, respectively, but not at 30 months in three of four patients.
Intracerebral rAVV2/5 was well tolerated and induced sustained enzyme production in the brain. The initial specific anti-NAGLU immune response that later subsided suggested acquired immunological tolerance. The best results being obtained in the youngest patient implies a potential window of opportunity. Longer follow-up is needed to further assess safety outcomes and persistence of improved cognitive development.
Association Française Contre les Myopathies, Vaincre les Maladies Lysosomales, Institut Pasteur, and UniQure.
黏多糖贮积症 IIIB 型综合征（也称为 Sanfilippo 型 B 综合征）是一种溶酶体贮积病，导致 2-4 岁后认知能力逐渐下降。目前尚无针对该疾病神经表现的治疗方法。我们试图评估一种新型脑内基因治疗的安全性和疗效。
法国当地监管机构允许本项 1/2 期研究纳入最多 4 名儿童。治疗方法为 16 个局部脑内沉积（小脑内 4 个）重组腺相关病毒血清型 2/5（rAAV2/5），编码人α-N-乙酰氨基葡萄糖苷酶（NAGLU），同时联合免疫抑制治疗。术后 30 个月，我们评估了耐受性、神经认知进展、脑生长、CSF 中 NAGLU 酶活性和特异性抗-NAGLU 免疫反应。本试验在 EudraCT 注册，编号为 2012-000856-33，在国际标准临床试验注册平台注册，编号为 ISRCTN19853672。
7 名符合条件的儿童中，年龄分别为 20、26、30 和 53 个月的来自法国（n=2）、意大利（n=1）和希腊（n=1）的 4 名最年幼的儿童于 2012 年 2 月至 2014 年 2 月间入组。共记录 125 次不良事件，其中 117 次为治疗相关，包括 6 例严重不良事件，但未观察到疑似意外严重药物不良反应。术后 2 天在血液中检测到载体基因组。与黏多糖贮积症 III 型的自然病程相比，所有患者的神经认知进展均有所改善，最年轻的患者的功能接近健康儿童。与疾病自然病程相比，患者 1 的发育商下降了 11.0 分，患者 2 下降了 23.0 分，患者 3 下降了 29.0 分，患者 4 下降了 17.0 分。在腰椎 CSF 中检测到 NAGLU 活性，为正常儿童的 15-20%。体外暴露于 NAGLU 抗原后增殖并产生肿瘤坏死因子 α 的循环 T 淋巴细胞可分别在 1-12 个月和 3-12 个月时检测到，但在 4 名患者中的 3 名中，30 个月时无法检测到。
脑内 rAAV2/5 耐受性良好，可在脑内持续产生酶。最初的特异性抗-NAGLU 免疫反应随后减弱，提示获得了免疫耐受。在最年轻的患者中获得了最佳结果，表明存在潜在的机会窗口。需要更长时间的随访来进一步评估安全性和认知改善的持久性。
法国肌肉疾病协会、战胜溶酶体贮积病协会、巴斯德研究所和 UniQure。
