Treatment of late infantile neuronal ceroid lipofuscinosis by CNS administration of a serotype 2 adeno-associated virus expressing CLN2 cDNA
Treatment of late infantile neuronal ceroid lipofuscinosis by CNS administration of a serotype 2 adeno-associated virus expressing CLN2 cDNA
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DOI：
10.1089/hum.2008.022
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发表时间：
2008-05-01
影响因子：
4.2
通讯作者：
Crystal, Ronald G.
中科院分区：
文献类型：
--
作者：
Worgall, Stefan;Sondhi, Dolan;Crystal, Ronald G.
晚期婴儿神经性ceroid lipofuscinosis （LINCL）是一种常染色体隐性，影响中枢神经系统的神经退行性溶酶体贮积病，在8至12岁时致命。将表达人CLN2 cDNA的腺相关病毒（AAV） 2型血清型载体（AAV2(CU)h-CLN2）的总平均剂量2.5 × 10（12）个粒子单位给予10例LINCL患儿中枢神经系统的12个部位。除了安全性参数外，还使用神经系统评分量表（主要变量）和三个定量磁共振成像（MRI）参数（次要变量）来比较治疗组与未治疗组18个月的神经功能衰退率。虽然没有意外的严重不良事件明确归因于AAV2(CU)hCLN2载体，但有严重的不良反应，其病因在实验条件下无法确定。一名受试者在术后第14天出现癫痫持续状态后49天死亡，但没有中枢神经系统炎症的证据。10名受试者中有4人对病媒产生了轻微的、大多是短暂的体液反应。与对照组相比，测量到的所有MRI参数的下降速度较慢，尽管数量太小，没有统计学意义。重要的是，作为主要结果变量的神经评分量表的评估显示，与对照组相比，下降率显著降低。尽管该试验没有匹配、随机或盲法，并且缺乏同期安慰剂/假对照组，但对主要结局变量的评估表明，在接受治疗的儿童中，LINCL的进展有所减缓。在此基础上，我们建议有必要进行更多的研究来评估aav介导的LINCL基因治疗的安全性和有效性。
Late infantile neuronal ceroid lipofuscinosis (LINCL) is an autosomal recessive, neurodegenerative lysosomal storage disease affecting the CNS and is fatal by age 8 to 12 years. A total average dose of 2.5 x 10(12) particle units of an adeno-associated virus (AAV) serotype 2 vector expressing the human CLN2 cDNA (AAV2(CU)h-CLN2) was administered to 12 locations in the CNS of 10 children with LINCL. In addition to safety parameters, a neurological rating scale (primary variable) and three quantitative magnetic resonance imaging (MRI) parameters (secondary variables) were used to compare the rate of neurological decline for 18 months in treated subjects compared with untreated subjects. Although there were no unexpected serious adverse events that were unequivocally attributable to the AAV2(CU)hCLN2 vector, there were serious adverse effects, the etiology of which could not be determined under the conditions of the experiment. One subject died 49 days postsurgery after developing status epilepticus on day 14, but with no evidence of CNS inflammation. Four of the 10 subjects developed a mild, mostly transient, humoral response to the vector. Compared with control subjects, the measured rates of decline of all MRI parameters were slower, albeit the numbers were too small for statistical significance. Importantly, assessment of the neurologic rating scale, which was the primary outcome variable, demonstrated a significantly reduced rate of decline compared with control subjects. Although the trial is not matched, randomized, or blinded and lacked a contemporaneous placebo/sham control group, assessment of the primary outcome variable suggests a slowing of progression of LINCL in the treated children. On this basis, we propose that additional studies to assess the safety and efficacy of AAV-mediated gene therapy for LINCL are warranted.