Mucopolysaccharidosis type IIIA (MPS IIIA, Sanfilippo A syndrome) is a single gene (SGSH) childhood onset neurodegenerative disease for which gene therapy is in clinical trial. Theoretically, the transfer of a working gene should enable functional expression of the defective protein and rescue the phenotype when administered before the onset of irreversible disease. Recombinant adeno-associated virus (AAV) is being used as a vehicle for a number of gene therapy applications and the neurotropism of serotype 9 affords utility for monogenetic neurological disorders. To assess the efficacy of restoring the underlying biochemistry in the MPS IIIA brain, tail vein injections of self-complementary AAV9 human N-sulfoglucosamine sulfohydrolase (scAAV9.U1A.hSGSH) at 3 × 10¹³ vg/kg were administered to 6- and 16-week-old MPS IIIA mice. Heparan sulfate (HS) and G_M2 and G_M3 gangliosides were cleared from the cortex, hippocampus and subcortex with residual storage remaining in the brain stem and cerebellum. SGSH activity increased in the brain of the MPS IIIA-treated mice, but remained significantly reduced compared with wild-type. Motor activity as assessed in an open-field arena, and gait length, improved in MPS IIIA mice treated at both 6 and 16 weeks of age. However, functional assessment of cognition in the water cross-maze test, as well as gait width, normalized in mice treated at 6 weeks of age only, with mice treated at 16 weeks performing similar to untreated MPS IIIA mice. Astrogliosis was reduced in mice treated at 6 and 16 weeks of age compared to untreated MPS IIIA mice. These results demonstrate that the gene product is actively clearing primary HS and secondary ganglioside accumulation in MPS IIIA mice, but in older mice, neurocognitive impairments remain. This is likely due to secondary downstream consequences of HS affecting neurological functions that are not reversible upon substrate clearance.

中文翻译：

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全身性 scAAV9.U1a.hSGSH 递送可纠正疾病早期和晚期粘多糖贮积症 IIIA 型的脑生化

粘多糖贮积症 IIIA 型（MPS IIIA，Sanfilippo A 综合征）是一种单基因 ( SGSH ) 儿童期发病的神经退行性疾病，基因治疗正在临床试验中。从理论上讲，工作基因的转移应该能够在不可逆疾病发作之前进行有缺陷的蛋白质的功能性表达并挽救表型。重组腺相关病毒 (AAV) 被用作许多基因治疗应用的载体，血清型 9 的神经嗜性为单基因神经系统疾病提供了实用性。^{为了评估在 MPS IIIA 大脑中恢复基础生化的功效，尾静脉注射 3 × 10 13}的自我互补 AAV9 人N-磺基葡糖胺磺基水解酶 (scAAV9.U1A.hSGSH)将 vg/kg 施用于 6 周和 16 周龄的 MPS IIIA 小鼠。硫酸乙酰肝素 (HS) 和 G _M2和 G _M3神经节苷脂从皮层、海马和皮层下被清除，残留储存在脑干和小脑中。经 MPS IIIA 处理的小鼠大脑中 SGSH 活性增加，但与野生型相比仍显着降低。在 6 周龄和 16 周龄治疗的 MPS IIIA 小鼠中，在开放场地评估的运动活动和步态长度都有所改善。然而，水交叉迷宫测试中的认知功能评估，以及步态宽度，仅在 6 周龄处理的小鼠中正常化，16 周处理的小鼠表现与未处理的 MPS IIIA 小鼠相似。与未治疗的 MPS IIIA 小鼠相比，在 6 周龄和 16 周龄时接受治疗的小鼠的星形胶质细胞增生减少。这些结果表明该基因产物正在积极清除 MPS IIIA 小鼠中的原发性 HS 和继发性神经节苷脂积累，但在老年小鼠中，神经认知障碍仍然存在。这可能是由于 HS 的继发性下游后果影响了在底物清除后不可逆的神经功能。