CLN2 disease is a fatal, childhood autosomal recessive disorder caused by mutations in ceroid lipofuscinosis type 2 (CLN2) gene, encoding tripeptidyl peptidase 1 (TPP-1). Loss of TPP-1 activity leads to accumulation of storage material in lysosomes and resultant neuronal cell death with neurodegeneration. Genotype/phenotype comparisons suggest that the phenotype should be ameliorated with increase of TPP-1 levels to 5-10% of normal with wide central nervous system (CNS) distribution. Our previous clinical study showed that intraparenchymal (IPC) administration of AAVrh.10hCLN2, an adeno-associated vector serotype rh.10 encoding human CLN2, slowed, but did not stop disease progression, suggesting that this may be insufficient to distribute the therapy throughout the CNS (Sondhi 2020). In this study, we assessed whether the less invasive intracisternal delivery route would be safe and provide a wider distribution of TPP-1. A study was conducted in nonhuman primates (NHPs) with intracisternal delivery to cerebrospinal fluid (CSF) of AAVrh.10hCLN2 (5 × 1013 genome copies) or phosphate buffered saline (PBS). No abnormal behavior was noted. CNS magnetic resonance imaging and clinical chemistry data were all unremarkable. Histopathology of major organs had no abnormal finding attributable to the intervention or the vector, except that in one out of two animals treated with AAVrh.10hCLN2, dorsal root ganglia showed mild-to-moderate mononuclear cell infiltrates and neuronal degeneration. In contrast to our previous NHP study (Sondhi 2012) with IPC administration where TPP-1 activity was >2 × above controls in 30% of treated brains, in the two intracisternal treated NHPs, the TPP-1 activity was >2 × above controls in 50% and 41% of treated brains, and 52% and 84% of brain had >1,000 vector genomes/μg DNA, compared to 0% in the two PBS NHP. CSF TPP1 levels in treated animals were 43-62% of normal human levels. Collectively, these data indicate that AAVrh.10hCLN2 delivered by intracisternal route is safe and widely distributes TPP-1 in brain and CSF at levels that are potentially therapeutic. Clinical Trial Registration: NCT02893826, NCT04669535, NCT04273269, NCT03580083, NCT04408625, NCT04127578, and NCT04792944.

中文翻译：

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非人灵长类动物脑池内给药治疗 CLN2 Batten 病后 AAVrh.10hCLN2 的安全性和生物分布评估。

CLN2 病是一种致命的儿童常染色体隐性遗传病，由编码三肽基肽酶 1 (TPP-1) 的 2 型蜡质脂褐质沉着症 (CLN2) 基因突变引起。TPP-1 活性的丧失导致溶酶体中储存物质的积累，并导致神经元细胞死亡和神经变性。基因型/表型比较表明，随着 TPP-1 水平增加至正常值的 5-10%，表型应得到改善，并具有广泛的中枢神经系统 (CNS) 分布。我们之前的临床研究表明，AAVrh.10hCLN2（一种编码人 CLN2 的腺相关载体血清型 rh.10）的实质内 (IPC) 给药可减缓但并未阻止疾病进展，这表明这可能不足以在整个过程中分配治疗。中枢神经系统（Sondhi 2020）。在这项研究中，我们评估了侵入性较小的脑池内给药途径是否安全并提供更广泛的 TPP-1 分布。在非人灵长类动物 (NHP) 中进行了一项研究，将 AAVrh.10hCLN2（5 × 1013 基因组拷贝）或磷酸盐缓冲盐水 (PBS) 脑池内输送至脑脊液 (CSF)。没有发现异常行为。中枢神经系统磁共振成像和临床化学数据均无异常。主要器官的组织病理学没有发现可归因于干预或载体的异常发现，但在用 AAVrh.10hCLN2 治疗的两只动物中，有一只的背根神经节显示出轻度至中度的单核细胞浸润和神经元变性。与我们之前采用 IPC 给药的 NHP 研究（Sondhi 2012）相比，其中 30% 的治疗大脑中 TPP-1 活性高于对照 2 倍以上，而在两个脑池内治疗的 NHP 中，TPP-1 活性高于对照 2 倍以上50% 和 41% 的接受治疗的大脑中，52% 和 84% 的大脑具有 >1,000 个载体基因组/μg DNA，而两种 PBS NHP 中的这一比例为 0%。接受治疗的动物脑脊液 TPP1 水平为正常人类水平的 43-62%。总的来说，这些数据表明，通过脑池内途径递送的 AAVrh.10hCLN2 是安全的，并且 TPP-1 以潜在治疗水平广泛分布在大脑和脑脊液中。临床试验注册：NCT02893826、NCT04669535、NCT04273269、NCT03580083、NCT04408625、NCT04127578和NCT04792944。