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Research Article

使用静脉内自互补己糖胺酶载体治疗成年 Sandhoff 小鼠 GM2 神经节苷脂沉积症

卷 22, 期 3, 2022

发表于: 24 November, 2021

页: [262 - 276] 页: 15

弟呕挨: 10.2174/1566523221666210916153051

价格: $65

摘要

背景：GM2 神经节苷脂沉积症是一种由 β-氨基己糖苷酶 A 酶 (Hex A)（一种 α/β-亚基异二聚体）缺乏引起的神经退行性溶酶体贮积病。由 HEX M 编码的人类氨基己糖苷酶 α 亚基的新变体先前已被证明可形成稳定的同型二聚体 Hex M，可在体内水解 GM2 神经节苷脂 (GM2)。 材料与方法：目前的研究评估了静脉内 (IV) 递送结合 HEXM 转基因 scAAV9/HEXM 的自我互补腺相关病毒血清型 9 (scAAV9) 载体的功效，包括基于提供给研究人员的剂量的结果。桑霍夫 (SD) 小鼠。六周大的 SD 小鼠被注射 2.5E+12 载体基因组（低剂量，LD）或 1.0E+13vg（高剂量，HD）。我们假设，在检查成年 SD 小鼠中 scAAV9/HEXM 的剂量比较时，HD 组将比 LD 组有更多的有益结果。评估包括生存、行为结果、载体生物分布和中枢神经系统内的酶活性。 结果：在 HD 队列中观察到毒性，14 只小鼠中有 8 只在注射后一个月内死亡。与具有 16 周典型生存期的未治疗 SD 小鼠相比，LD 组和剩余的 HD 小鼠具有显着的生存获益，平均/中位生存期分别为 40.6/34.5 和 55.9/56.7 周。还观察到显着的行为、生化和分子益处。该研究的第二个目的是研究静脉输注甘露醇对 LD scAAV9/HEXM 载体的生物分布和 SD 小鼠存活的影响。观察到载体的生物分布以及生存益处（平均/中位数为 41.6/49.3 周）均有所增加。 结论：这些结果证明了使用 IV 递送的 AAV 载体治疗 GM2 神经节苷脂沉积症的潜在益处和严重局限性。

关键词: Sandhoff，tay sachs，基因治疗，AAV，腺相关病毒，己糖胺酶 A，GM2 神经节苷脂，GM2 神经节苷脂

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