AAV9 Gene Therapy Increases Lifespan and Treats Pathological and Behavioral Abnormalities in a Mouse Model of CLN8-Batten Disease
AAV9 Gene Therapy Increases Lifespan and Treats Pathological and Behavioral Abnormalities in a Mouse Model of CLN8-Batten Disease
复制标题
DOI：
10.1016/j.ymthe.2020.09.033
复制
发表时间：
2021-01-06
影响因子：
12.4
通讯作者：
Weimer, Jill M.
中科院分区：
文献类型：
--
作者：
Johnson, Tyler B.;White, Katherine A.;Weimer, Jill M.
CLN 8疾病是由CLN 8基因中的双等位基因突变引起的神经元蜡样质脂褐质沉积症的一种罕见形式，CLN 8基因编码参与溶酶体酶运输的跨膜内质网蛋白。CLN 8疾病患者表现为肌阵挛、强直-阵挛性癫痫发作以及认知和运动功能的进行性下降，其中许多病例导致生命早期的过早死亡。目前还没有治疗方法可以治愈这种疾病或大大减缓疾病进展。使用CLN 8疾病的小鼠模型，我们测试了脑室内（i. c. v.）递送驱动人CLN 8表达的自身互补腺相关病毒血清型9（scAAV 9）基因治疗载体。单次新生儿注射是安全的，耐受性良好，导致从4至24个月在整个CNS中稳健的转基因表达，减少疾病的组织病理学和行为特征，并将寿命从未治疗动物的10个月恢复到治疗动物的24个月以上。虽然尚不清楚这些行为改善中的一些是否与保留的视觉功能、学习/记忆的改善或其他中枢或外周益处有关，但这些结果证明了迄今为止在CLN 8疾病动物模型中报道的最成功的拯救程度，并且它们支持进一步开发针对这种疾病的基因疗法。
CLN8 disease is a rare form of neuronal ceroid lipofuscinosis caused by biallelic mutations in the CLN8 gene, which encodes a transmembrane endoplasmic reticulum protein involved in trafficking of lysosomal enzymes. CLN8 disease patients present with myoclonus, tonic-clonic seizures, and progressive declines in cognitive and motor function, with many cases resulting in premature death early in life. There are currently no treatments that can cure the disease or substantially slow disease progression. Using a mouse model of CLN8 disease, we tested the safety and efficacy of an intracerebroventricularly (i.c.v.) delivered self-complementary adeno-associated virus serotype 9 (scAAV9) gene therapy vector driving expression of human CLN8. A single neonatal injection was safe and well tolerated, resulting in robust transgene expression throughout the CNS from 4 to 24 months, reducing histopathological and behavioral hallmarks of the disease and restoring lifespan from 10 months in untreated animals to beyond 24 months of age in treated animals. While it is unclear whether some of these behavioral improvements relate to preserved visual function, improvements in learning/memory, or other central or peripheral benefits, these results demonstrate, by far, the most successful degree of rescue reported in an animal model of CLN8 disease, and they support further development of gene therapy for this disorder.