Department of Medicinal Biotechnology, Institute for Medicinal Research, Graduate School of Pharmaceutical Sciences, The University of Tokushima, Tokushima, Japan.
Ann Neurol. 2011 Apr;69(4):691-701. doi: 10.1002/ana.22262. Epub 2010 Dec 8.
Novel recombinant human lysosomal β-hexosaminidase A (HexA) was developed for enzyme replacement therapy (ERT) for Tay-Sachs and Sandhoff diseases, ie, autosomal recessive GM2 gangliosidoses, caused by HexA deficiency.
A recombinant human HexA (Om4HexA) with a high mannose 6-phosphate (M6P)-type-N-glycan content, which was produced by a methylotrophic yeast strain, Ogataea minuta, overexpressing the OmMNN4 gene, was intracerebroventricularly (ICV) administered to Sandhoff disease model mice (Hexb⁻/⁻ mice) at different doses (0.5-2.5 mg/kg), and then the replacement and therapeutic effects were examined.
The Om4HexA was widely distributed across the ependymal cell layer, dose-dependently restored the enzyme activity due to uptake via cell surface cation-independent M6P receptor (CI-M6PR) on neural cells, and reduced substrates, including GM2 ganglioside (GM2), asialo GM2 (GA2), and oligosaccharides with terminal N-acetylglucosamine residues (GlcNAc-oligosaccharides), accumulated in brain parenchyma. A significant inhibition of chemokine macrophage inflammatory protein-1 α (MIP-1α) induction was also revealed, especially in the hindbrain (< 63%). The decrease in central neural storage correlated with an improvement of motor dysfunction as well as prolongation of the lifespan.
This lysosome-directed recombinant human enzyme drug derived from methylotrophic yeast has the high therapeutic potential to improve the motor dysfunction and quality of life of the lysosomal storage diseases (LSDs) patients with neurological manifestations. We emphasize the importance of neural cell surface M6P receptor as a delivery target of neural cell-directed enzyme replacement therapy (NCDERT) for neurodegenerative metabolic diseases.
新型重组人溶酶体β-己糖胺酶 A（HexA）被开发用于酶替代疗法（ERT）治疗泰-萨克斯病和桑德霍夫病，即由 HexA 缺乏引起的常染色体隐性 GM2 神经节苷脂贮积症。
使用甲基营养酵母菌株 Ogataea minuta 过量表达 OmMNN4 基因生产的具有高甘露糖 6-磷酸（M6P）型-N-聚糖含量的重组人 HexA（Om4HexA），通过脑室内（ICV）给予不同剂量（0.5-2.5mg/kg）的桑德霍夫病模型小鼠（Hexb⁻/⁻ 小鼠），然后检查替代和治疗效果。
Om4HexA 广泛分布于室管膜细胞层，通过神经细胞表面阳离子非依赖性 M6P 受体（CI-M6PR）摄取，剂量依赖性地恢复了由于摄取而导致的酶活性，并减少了脑实质中积累的底物，包括 GM2 神经节苷脂（GM2）、去唾液酸 GM2（GA2）和末端 N-乙酰葡萄糖胺残基（GlcNAc-寡糖）的寡糖。还发现趋化因子巨噬细胞炎性蛋白-1α（MIP-1α）诱导的显著抑制，尤其是在后脑（<63%）。中枢神经储存的减少与运动功能障碍的改善以及寿命的延长相关。
这种源自甲基营养酵母的溶酶体定向重组人酶药物具有改善有神经表现的溶酶体贮积症（LSD）患者运动功能障碍和生活质量的高治疗潜力。我们强调神经细胞表面 M6P 受体作为神经细胞定向酶替代疗法（NCDERT）治疗神经退行性代谢疾病的重要性。
