Alexander disease (AxD) is a devastating leukodystrophy caused by gain-of-function mutations in GFAP, and the only available treatments are supportive. Recent advances in antisense oligonucleotide (ASO) therapy have demonstrated that transcript targeting can be a successful strategy for human neurodegenerative diseases amenable to this approach. We have previously used mouse models of AxD to show that Gfap-targeted ASO suppresses protein accumulation and reverses pathology; however, the mice have a mild phenotype with no apparent leukodystrophy or overt clinical features and are therefore limited for assessing functional outcomes. In this report, we introduce a rat model of AxD that exhibits hallmark pathology with GFAP aggregation in the form of Rosenthal fibers, widespread astrogliosis, and white matter deficits. These animals develop normally during the first postnatal weeks but fail to thrive after weaning and develop severe motor deficits as they mature, with about 14% dying of unknown cause between 6 and 12 weeks of age. In this model, a single treatment with Gfap-targeted ASO provides long-lasting suppression, reverses GFAP pathology, and, depending on age of treatment, prevents or mitigates white matter deficits and motor impairment. In this report, we characterize an improved animal model of AxD with myelin pathology and motor impairment, recapitulating prominent features of the human disease, and use this model to show that ASO therapy has the potential to not only prevent but also reverse many aspects of disease.

中文翻译：

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亚历山大病大鼠模型中的反义疗法可逆转 GFAP 病理学、白质缺陷和运动障碍

亚历山大病 (AxD) 是一种由GFAP功能获得性突变引起的破坏性脑白质营养不良，唯一可用的治疗方法是支持性的。反义寡核苷酸 (ASO) 疗法的最新进展表明，转录物靶向可以成为适用于这种方法的人类神经退行性疾病的成功策略。我们之前使用 AxD 的小鼠模型来证明Gfap-靶向 ASO 抑制蛋白质积累并逆转病理；然而，这些小鼠具有轻微的表型，没有明显的白质营养不良或明显的临床特征，因此在评估功能结果方面受到限制。在本报告中，我们介绍了一种 AxD 大鼠模型，该模型表现出以罗森塔尔纤维、广泛星形胶质细胞增生和白质缺陷形式出现的 GFAP 聚集的标志性病理学。这些动物在出生后的最初几周内发育正常，但在断奶后无法茁壮成长，并在它们成熟时出现严重的运动缺陷，大约 14% 的动物在 6 至 12 周龄之间死于不明原因。在此模型中，使用Gfap进行单次处理-靶向 ASO 提供持久抑制，逆转 GFAP 病理学，并且根据治疗年龄，预防或减轻白质缺陷和运动障碍。在本报告中，我们描述了具有髓鞘病理和运动障碍的 AxD 改进动物模型，概括了人类疾病的突出特征，并使用该模型表明 ASO 疗法不仅可以预防而且可以逆转疾病的许多方面.