Science：对海绵状脑白质营养不良症的基因疗法

来自一个进行了长达10年的临床试验的新结果指出，基因疗法是罹患海绵状脑白质营养不良症（Canavan Disease）儿童的一个可行的治疗选项，该疾病是一种出生时便开始的神经退行性疾病。罹患海绵状脑白质营养不良症（Canavan Disease）的人缺乏天冬酰转移酶（aspartoacylase enzyme），它是由ASPA基因产生的。没有这种酶，他们无法在脑中分解N-乙酰基天冬氨酸或NAA。随后的NAA的积聚阻止了髓磷脂的发育，而髓磷脂是包围神经细胞的保护鞘。这些发现提供的证据表明，用腺相关病毒载体的基因疗法是安全的，它能使脑中的NAA浓度正常并减缓脑的萎缩。Paola Leone及其同事用基因疗法为13名年轻的患者输送一个有功能的ASPA 基因的拷贝。他们将该基因装入一种腺相关病毒载体。在注射之后，该病毒载体与神经元细胞膜结合并被包入囊中而进入细胞。一旦进入细胞，该基因会表达而产生可分解NAA的天冬酰转移酶（aspartoacylase enzyme）。该研究团队在试验结束后对病人进行了5年的监测并看到病人脑内NAA浓度下降、癫痫发作频率下降以及髓磷脂产生的增加。没有严重副作用的报道。如今，所有患者都活着，且他们的生活品质都得到了改善。这些结果显示，基因疗法对于治疗海绵状脑白质营养不良症（Canavan Disease）可以是安全有效的。文章的作者写道，在婴儿期早期发现该病并用基因疗法进行治疗可为病人提供最佳的减少症状和维持神经系统功能长期稳定的机会

DOI: 10.1126/scitranslmed.3003454
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Long-Term Follow-Up After Gene Therapy for Canavan Disease

Paola Leone1,*, David Shera2, Scott W.J. McPhee3, Jeremy S. Francis1, Edwin H. Kolodny4, Larissa T. Bilaniuk5, Dah-Jyuu Wang5, Mitra Assadi6, Olga Goldfarb6, H. Warren Goldman6, Andrew Freese7, Deborah Young8, Matthew J. During8,9, R. Jude Samulski3,10 and Christopher G. Janson7,11

Canavan disease is a hereditary leukodystrophy caused by mutations in the aspartoacylase gene (ASPA), leading to loss of enzyme activity and increased concentrations of the substrate N-acetyl-aspartate (NAA) in the brain. Accumulation of NAA results in spongiform degeneration of white matter and severe impairment of psychomotor development. The goal of this prospective cohort study was to assess long-term safety and preliminary efficacy measures after gene therapy with an adeno-associated viral vector carrying the ASPA gene (AAV2-ASPA). Using noninvasive magnetic resonance imaging and standardized clinical rating scales, we observed Canavan disease in 28 patients, with a subset of 13 patients being treated with AAV2-ASPA. Each patient received 9 × 1011 vector genomes via intraparenchymal delivery at six brain infusion sites. Safety data collected over a minimum 5-year follow-up period showed a lack of long-term adverse events related to the AAV2 vector. Posttreatment effects were analyzed using a generalized linear mixed model, which showed changes in predefined surrogate markers of disease progression and clinical assessment subscores. AAV2-ASPA gene therapy resulted in a decrease in elevated NAA in the brain and slowed progression of brain atrophy, with some improvement in seizure frequency and with stabilization of overall clinical status.