Substrate reduction therapy for Krabbe disease and metachromatic leukodystrophy using a novel ceramide galactosyltransferase inhibitor.
Substrate reduction therapy for Krabbe disease and metachromatic leukodystrophy using a novel ceramide galactosyltransferase inhibitor.
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DOI：
10.1038/s41598-021-93601-1
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发表时间：
2021-07-14
影响因子：
4.6
通讯作者：
Crawford BE
中科院分区：
文献类型：
--
作者：
Babcock MC;Mikulka CR;Wang B;Chandriani S;Chandra S;Xu Y;Webster K;Feng Y;Nelvagal HR;Giaramita A;Yip BK;Lo M;Jiang X;Chao Q;Woloszynek JC;Shen Y;Bhagwat S;Sands MS;Crawford BE
Krabbe病（KD）和异染性脑白质营养不良（MLD）分别由糖脂半乳糖神经酰胺（GalCer）和硫苷脂及其毒性代谢物精神病肽和溶血硫苷脂的蓄积引起。我们发现了一种有效的和选择性的小分子抑制剂（S202）的神经酰胺半乳糖基转移酶（CGT），GalCer生物合成的关键酶，并表征其作为底物减少疗法（SRT）的用途。用S202剂量依赖性地处理KD小鼠模型减少了中枢（CNS）和外周（PNS）神经系统中的GalCer和精神病碱，并显著增加了寿命。类似地，治疗MLD小鼠模型降低了硫苷脂和溶血硫苷脂水平。有趣的是，较低剂量的S202部分地抑制CGT，并选择性地减少非羟基化形式的GalCer和硫苷脂的合成，这似乎是精神病肽和溶血硫苷脂的主要来源。较高剂量的S202更完全地抑制CGT，并降低GalCer和硫苷脂的非羟基化和羟基化形式的水平。尽管在KD和MLD的鼠模型中观察到显著的益处，但慢性CGT抑制对野生型小鼠的CNS和PNS都有负面影响。因此，有必要进一步研究以阐明CGT抑制的全部治疗潜力。
Krabbe disease (KD) and metachromatic leukodystrophy (MLD) are caused by accumulation of the glycolipids galactosylceramide (GalCer) and sulfatide and their toxic metabolites psychosine and lysosulfatide, respectively. We discovered a potent and selective small molecule inhibitor (S202) of ceramide galactosyltransferase (CGT), the key enzyme for GalCer biosynthesis, and characterized its use as substrate reduction therapy (SRT). Treating a KD mouse model with S202 dose-dependently reduced GalCer and psychosine in the central (CNS) and peripheral (PNS) nervous systems and significantly increased lifespan. Similarly, treating an MLD mouse model decreased sulfatides and lysosulfatide levels. Interestingly, lower doses of S202 partially inhibited CGT and selectively reduced synthesis of non-hydroxylated forms of GalCer and sulfatide, which appear to be the primary source of psychosine and lysosulfatide. Higher doses of S202 more completely inhibited CGT and reduced the levels of both non-hydroxylated and hydroxylated forms of GalCer and sulfatide. Despite the significant benefits observed in murine models of KD and MLD, chronic CGT inhibition negatively impacted both the CNS and PNS of wild-type mice. Therefore, further studies are necessary to elucidate the full therapeutic potential of CGT inhibition.
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DOI：
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发表时间：
2018-06-04
期刊：
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影响因子：
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