Metachromatic leukodystrophy, a fatal pediatric neurodegenerative lysosomal storage disease caused by mutations in the arylsulfatase A (ARSA) gene, is characterized by intracellular accumulation of sulfatides in the lysosomes of cells of the central nervous system (CNS). In previous studies, we have demonstrated efficacy of AAVrh.10hARSA, an adeno-associated virus (AAV) serotype rh.10 vector coding for the human ARSA gene to the CNS of a mouse model of the disease, and that catheter-based intraparenchymal administration of AAVrh.10hARSA to the CNS of nonhuman primates (NHPs) white matter results in widespread expression of ARSA. As a formal dose-escalating safety/toxicology study, we assessed the safety of intraparenchymal delivery of AAVrh.10hARSA vector to 12 sites in the white matter of the CNS of NHPs at 2.85 × 10¹⁰ (total low dose, 2.4 × 10⁹ genome copies [gc]/site) and 1.5 × 10¹² (total high dose, 1.3 × 10¹¹ gc/site) gc, compared to AAVrh.10Null (1.5 × 10¹² gc total, 1.3 × 10¹¹ gc/site) as a vector control, and phosphate buffered saline for a sham surgical control. No significant adverse effects were observed in animals treated with low dose AAVrh.10hARSA. However, animals treated with the high dose AAVrh.10ARSA and the high dose Null vector had highly localized CNS abnormalities on magnetic resonance imaging scans at the sites of catheter infusions, and histopathology demonstrated that these sites were associated with infiltrates of T cells, B cells, microglial cells, and/or macrophages. Although these findings had no clinical consequences, these safety data contribute to understanding the dose limits for CNS white matter direct intraparenchymal administration of AAVrh.10 vectors for treatment of CNS disorders.

中文翻译：

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直接脑实质内 AAVrh.10 介导的中枢神经系统基因治疗异染性脑白质营养不良的安全性

异染性脑白质营养不良是一种致命的小儿神经退行性溶酶体贮积病，由芳基硫酸酯酶 A ( ARSA ) 基因突变引起，其特征是中枢神经系统 (CNS) 细胞溶酶体中硫脂的细胞内积累。在以前的研究中，我们已经证明了 AAVrh.10hARSA 的功效，这是一种腺相关病毒 (AAV) 血清型 rh.10 载体，编码人类ARSA基因到该疾病的小鼠模型的 CNS，并且基于导管的 AAVrh.10hARSA 对非人类灵长类动物 (NHP) 白质的 CNS 的实质内给药导致 ARSA 的广泛表达。作为正式的剂量递增安全性/毒理学研究，我们评估了将 AAVrh.10hARSA 载体以 2.85 × 10 ¹⁰（总低剂量，2.4 × 10 ⁹拷贝 [gc]/位点）和 1.5 × 10 ¹²（总高剂量，1.3 × 10 ¹¹ gc/位点）gc，与 AAVrh.10Null（1.5 × 10 ¹² gc 总数，1.3 × 10 ¹¹gc/site) 作为载体对照，磷酸盐缓冲盐水作为假手术对照。在用低剂量 AAVrh.10hARSA 治疗的动物中未观察到明显的不良反应。然而，用高剂量 AAVrh.10ARSA 和高剂量 Null 载体治疗的动物在导管输注部位的磁共振成像扫描中具有高度局部的 CNS 异常，组织病理学表明这些部位与 T 细胞、B 细胞的浸润有关、小胶质细胞和/或巨噬细胞。尽管这些发现没有临床后果，但这些安全性数据有助于了解 CNS 白质直接脑实质内给予 AAVrh.10 载体治疗 CNS 疾病的剂量限制。