Oral monosaccharide therapies to reverse renal and muscle hyposialylation in a mouse model of GNE myopathy.
Oral monosaccharide therapies to reverse renal and muscle hyposialylation in a mouse model of GNE myopathy.
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DOI：
10.1016/j.ymgme.2012.10.011
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发表时间：
2012-12
影响因子：
3.8
通讯作者：
Huizing, Marjan
中科院分区：
文献类型：
--
作者：
Niethamer, Terren K.;Yardeni, Tal;Leoyklang, Petcharat;Ciccone, Carla;Astiz-Martinez, Adrian;Jacobs, Katherine;Dorward, Heidi M.;Zerfas, Patricia M.;Gahl, William A.;Huizing, Marjan
关键词：
GNE肌病，以前称为遗传性包涵体肌病（HIBM），是一种成人发病的神经肌肉疾病，其特征是进行性肌无力。这种疾病是由GNE中的双等位基因突变引起的，GNE编码UDP-N-乙酰葡糖胺2-差向异构酶/N-乙酰甘露糖胺激酶，唾液酸合成的关键酶。与聚糖唾液酸化受损相关的GNE肌病尚无获批治疗。在此，我们通过评估GNE肌病基因敲入小鼠模型（Gne p.M712T）的肾脏和肌肉低唾液酸化，测试潜在的唾液酸化增加单糖在预防（胚胎和新生儿阶段）和治疗（症状发作后）方面的有效性。我们证明，口服甘露糖胺（ManN），而不是唾液酸（Neu 5Ac），甘露糖（Man），半乳糖（Gal），或葡萄糖胺（GlcN），给予怀孕的雌性小鼠有一个类似的预防作用，肾功能减退，病理和突变后代的新生儿存活，如先前所示的N-乙酰甘露糖胺（ManNAc）治疗。ManN可以通过直接但未知的途径转化为ManNAc，或者可以通过另一种作用模式起作用。其他糖（Man、Gal、GlcN）可以不穿过胎盘屏障（Neu 5Ac）和/或可以能够直接增加唾液酸化。由于GNE肌病患者在症状发作后可能需要在成年期进行治疗，我们还向6个月大的突变型Gne p.M712T小鼠给予饮用水中的ManNAc（1或2 g/kg/天，持续12周）、Neu 5Ac（2 g/kg/天，持续12周）或ManN（2 g/kg/天，持续6周）。所有三种疗法都显著改善了肌肉和肾脏的唾液酸化不足，如凝集素组织化学的总体唾液酸化状态和特异性唾液蛋白的免疫印迹所证明的。这些临床前数据强烈支持进一步评价口服ManNAc、Neu 5Ac和ManN作为GNE肌病的治疗，并且可以想象，其用于某些具有低唾液酸化的肾小球疾病。
GNE myopathy, previously termed hereditary inclusion body myopathy (HIBM), is an adult-onset neuromuscular disorder characterized by progressive muscle weakness. The disorder results from biallelic mutations in GNE, encoding UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, the key enzyme of sialic acid synthesis. GNE myopathy, associated with impaired glycan sialylation, has no approved therapy. Here we test potential sialylation-increasing monosaccharides for their effectiveness in prophylaxis (at the embryonic and neonatal stages) and therapy (after the onset of symptoms) by evaluating renal and muscle hyposialylation in a knock-in mouse model (Gne p.M712T) of GNE myopathy. We demonstrate that oral mannosamine (ManN), but not sialic acid (Neu5Ac), mannose (Man), galactose (Gal), or glucosamine (GlcN), administered to pregnant female mice has a similar prophylactic effect on renal hyposialylation, pathology and neonatal survival of mutant offspring, as previously shown for N-acetylmannosamine (ManNAc) therapy. ManN may be converted to ManNAc by a direct, yet unknown, pathway, or may act through another mode of action. The other sugars (Man, Gal, GlcN) may either not cross the placental barrier (Neu5Ac) and/or may be able to directly increase sialylation. Because GNE myopathy patients will likely require treatment in adulthood after onset of symptoms, we also administered ManNAc (1 or 2 g/kg/day for 12 weeks), Neu5Ac (2g/kg/day for 12 weeks), or ManN (2g/kg/day for 6 weeks) in drinking water to 6 month old mutant Gne p.M712T mice. All three therapies markedly improved the muscle and renal hyposialylation, as evidenced by lectin histochemistry for overall sialylation status and immunoblotting of specific sialoproteins. These preclinical data strongly support further evaluation of oral ManNAc, Neu5Ac and ManN as therapy for GNE myopathy and conceivably for certain glomerular diseases with hyposialylation.
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