X-linked adrenoleukodystrophy (X-ALD) is a rare, genetic disease in which increased very long chain fatty acids (VLCFAs) in the central nervous system (CNS) cause demyelination and axonopathy, leading to neurological deficits. Sobetirome, a potent thyroid hormone agonist, has been shown to lower VLCFAs in the periphery and CNS. In this study, two pharmacological strategies for enhancing the effects of sobetirome were tested in Abcd1 KO mice, a murine model with the same inborn error of metabolism as X-ALD patients. First, a sobetirome prodrug (Sob-AM2) with increased CNS penetration lowered CNS VLCFAs more potently than sobetirome and was better tolerated with reduced peripheral exposure. Second, co-administration of thyroid hormone with sobetirome enhanced VLCFA lowering in the periphery but did not produce greater lowering in the CNS. These data support the conclusion that CNS VLCFA lowering in Abcd1 knockout mice is limited by a mechanistic threshold related to slow lipid turnover.

中文翻译：

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药理补品弥补了脂质代谢的先天性错误。

X联肾上腺皮质营养不良（X-ALD）是一种罕见的遗传性疾病，其中中枢神经系统（CNS）中增加的超长链脂肪酸（VLCFA）引起脱髓鞘和轴突病变，导致神经功能缺损。Sobetirome是一种有效的甲状腺激素激动剂，已显示可降低外周和CNS中的VLCFA。在这项研究中，在Abcd1 KO小鼠中测试了两种提高sobetirome效果的药理策略，Abcd1 KO小鼠是一种小鼠模型，具有与X-ALD患者相同的先天代谢错误。首先，具有中枢神经系统渗透性增加的sobetirome前体药物（Sob-AM2）比sobetirome更有效地降低了CNS VLCFA，并且对外周暴露的耐受性更好。其次，甲状腺激素与钠bet的共同给药增强了外周VLCFA的降低，但在CNS中并未产生更大的降低。