Department of Genetics, Cell Biology and Development, University of Minnesota, USA; Molecular, Cellular, Developmental Biology & Genetics Graduate Program, University of Minnesota, USA; Gene Therapy Center, Department of Pediatrics, University of Minnesota, USA.
Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, USA; Gene Therapy Center, Department of Pediatrics, University of Minnesota, USA.
Mol Genet Metab. 2014 Feb;111(2):116-22. doi: 10.1016/j.ymgme.2013.09.008. Epub 2013 Sep 19.
Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disease that is systemic, including progressive neurodegeneration, mental retardation and death before the age of 10 years. MPS I results from deficiency of α-L-iduronidase (IDUA) in lysosomes and subsequent accumulation of glycosaminoglycans (GAG). Clinical enzyme replacement therapy (ERT) with intravenous laronidase reverses some aspects of MPS I disease (e.g., hepatomegaly, splenomegaly, glycosaminoglycanuria) and ameliorates others (e.g., pulmonary function, cardiac disease, arthropathy, exercise tolerance). However, neurologic benefits are thought to be negligible because the blood-brain barrier (BBB) blocks enzyme from reaching the central nervous system (CNS). We considered the possibility that a very high dose of intravenous laronidase might be able to traverse the BBB in small quantities, and provide some metabolic correction in the brain. To address this question, high-dose laronidase was administered (11.6 mg/kg, once per week, 4 weeks) to adult MPS I mice. IDUA enzyme activity in the cortex of treated mice increased to 97% of that in wild type mice (p<0.01). GAG levels in cortex were reduced by 63% of that from untreated MPS I mice (p<0.05). Further, immunohistochemical analysis showed that treatment reduced secondary GM3-ganglioside accumulation in treated MPS I mice. Water T-maze tests showed that the learning abnormality in MPS I mice was reduced (p<0.0001). In summary, repeated, high-dose ERT facilitated laronidase transit across the BBB, reduced GAG accumulation within the CNS, and rescued cognitive impairment.
黏多糖贮积症 I 型（MPS I）是一种常染色体隐性疾病，具有全身性，包括进行性神经退行性变、智力迟钝和 10 岁前死亡。MPS I 是由于溶酶体中α-L-艾杜糖苷酸酶（IDUA）缺乏，随后糖胺聚糖（GAG）积累所致。静脉注射拉罗尼酶的临床酶替代疗法（ERT）可逆转 MPS I 疾病的某些方面（例如肝肿大、脾肿大、糖胺聚糖尿症），并改善其他方面（例如肺功能、心脏病、关节病、运动耐量）。然而，神经学益处被认为是微不足道的，因为血脑屏障（BBB）阻止了酶到达中枢神经系统（CNS）。我们考虑了一种可能性，即非常高剂量的静脉注射拉罗尼酶可能能够以少量的量穿过 BBB，并为大脑提供一些代谢纠正。为了解决这个问题，给成年 MPS I 小鼠给予高剂量拉罗尼酶（11.6 mg/kg，每周一次，4 周）。治疗小鼠皮质中的 IDUA 酶活性增加到野生型小鼠的 97%（p<0.01）。皮质中的 GAG 水平降低了未治疗的 MPS I 小鼠的 63%（p<0.05）。此外，免疫组织化学分析表明，治疗减少了治疗的 MPS I 小鼠中继发性 GM3-神经节苷脂的积累。水 T 迷宫测试表明，MPS I 小鼠的学习异常得到了改善（p<0.0001）。总之，重复的高剂量 ERT 促进了拉罗尼酶穿过 BBB 的转运，减少了中枢神经系统内 GAG 的积累，并挽救了认知障碍。
