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Highly phosphomannosylated enzyme replacement therapy for GM2 gangliosidosis
Author(s) -
Tsuji Daisuke,
Akeboshi Hiromi,
Matsuoka Kazuhiko,
Yasuoka Hiroko,
Miyasaki Eri,
Kasahara Yoshiko,
Kawashima Ikuo,
Chiba Yasunori,
Jigami Yoshifumi,
Taki Takao,
Sakuraba Hitoshi,
Itoh Kohji
Publication year - 2011
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.22262
Subject(s) - gangliosidosis , enzyme replacement therapy , sandhoff disease , hexa , biology , ganglioside , biochemistry , tay sachs disease , enzyme , medicine , disease
Objective: 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. Methods: A recombinant human HexA ( Om4 HexA) 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 (0.5–2.5mg/kg), and then the replacement and therapeutic effects were examined. Results: The Om4 HexA 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. Interpretation: 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. ANN NEUROL 2010