Gene therapy to treat hereditary disorders conventionally delivers the normal allele to compensate for loss-of-function mutations. More effective gene therapy may be achieved using a gain-of-function variant. We tested the hypothesis that AAVrh.10-mediated CNS delivery of the human APOE2 allele with the Christchurch mutation (R136S) (E2Ch) will provide superior protection against APOE4-associated Alzheimer’s disease (AD) in mice compared to the unmodified APOE2 allele (E2). The vectors were assessed in two mouse strains with humanized APOE4: APP.PSEN1/TRE4 “amyloid mice” and P301S/TRE4, “tau mice.” Both the E2Ch and E2 vectors prevented Aβ42 and Aβ40 accumulation and decreased β-amyloid aggregates in amyloid mice, but only the E2Ch vector suppressed decreased tau tangles in tau mice. Microglial activation and reactive astrocytes were significantly suppressed by both vectors in amyloid mice but only the E2Ch vector mediated significant suppression of Iba1 and glial fibrillary acidic protein (GFAP) in tau mice. In four behavioral assays, the E2 and E2Ch vectors had similar benefits in amyloid mice, but E2Ch outperformed E2 in tau mice. In summary, while E2 is effective in suppressing amyloid pathology, the novel E2 variant E2Ch more effectively treats both the amyloid and tau pathology of murine AD in APOE4 background, supporting the development of AAVrh.10APOE2Ch as a therapy for APOE4-associated AD.

中文翻译：

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AAVrh.10 递送新型 APOE2-Christchurch 变体抑制阿尔茨海默病小鼠的淀粉样蛋白和 Tau 病理


治疗遗传性疾病的基因疗法通常提供正常的等位基因来补偿功能丧失突变。使用功能获得性变体可能实现更有效的基因治疗。我们检验了 AAVrh.10 介导的具有基督城突变 （R136S） （E2Ch） 的人类 APOE2 等位基因的 CNS 递送将在小鼠中为小鼠提供针对 APOE4 相关阿尔茨海默病 （AD） 的卓越保护与未修饰的 APOE2 等位基因 （E2）。在两种小鼠品系中用人源化 APOE4：APP 评估载体。PSEN1/TRE4 “淀粉样蛋白小鼠” 和 P301S/TRE4 “tau 小鼠”。E2Ch 和 E2 载体均阻止了淀粉样蛋白小鼠中 Aβ42 和 Aβ40 的积累并减少 β-淀粉样蛋白聚集体，但只有 E2Ch 载体抑制了 tau 小鼠中 tau 缠结的减少。在淀粉样蛋白小鼠中，两种载体都显著抑制了小胶质细胞活化和反应性星形胶质细胞，但只有 E2Ch 载体介导了 tau 小鼠中 Iba1 和神经胶质纤维酸性蛋白 （GFAP） 的显著抑制。在四种行为测定中，E2 和 E2Ch 载体在淀粉样蛋白小鼠中具有相似的好处，但 E2Ch 在 tau 小鼠中优于 E2。总之，虽然 E2 可有效抑制淀粉样蛋白病理，但新型 E2 变体 E2Ch 在 APOE4 背景下更有效地治疗小鼠 AD 的淀粉样蛋白和 tau 病理，支持 AAVrh.10APOE2Ch 作为 APOE4 相关 AD 疗法的开发。