title: Highly phosphomannosylated enzyme replacement therapy for GM2 gangliosidosis.
abstract: 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 (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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicinal Biotechnology, Institute for Medicinal Research, Graduate School of Pharmaceutical Sciences, The University of Tokushima, Tokushima, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tsuji
authors.forename: Hiromi
authors.initials: H
authors.lastname: Akeboshi
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Matsuoka
authors.forename: Hiroko
authors.initials: H
authors.lastname: Yasuoka
authors.forename: Eri
authors.initials: E
authors.lastname: Miyasaki
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Kasahara
authors.forename: Ikuo
authors.initials: I
authors.lastname: Kawashima
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Chiba
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Jigami
authors.forename: Takao
authors.initials: T
authors.lastname: Taki
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Sakuraba
authors.forename: Kohji
authors.initials: K
authors.lastname: Itoh
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D056947:Enzyme Replacement Therapy / Q000379:methods; D020143:Gangliosidoses, GM2 / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D054818:Hexosaminidase A / Q000008:administration & dosage* / Q000235:genetics; D054819:Hexosaminidase B / Q000235:genetics; D006801:Humans; D007276:Injections, Intraventricular; D008247:Lysosomes / Q000201:enzymology; D008359:Mannose-6-Phosphate Isomerase / Q000008:administration & dosage; D051379:Mice; D018345:Mice, Knockout; D054389:Receptors, CCR1 / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins; D012497:Sandhoff Disease / Q000188:drug therapy / Q000201:enzymology; D013661:Tay-Sachs Disease / Q000188:drug therapy / Q000235:genetics; D016896:Treatment Outcome; D015003:Yeasts
chemical_list: C515301:Ccr1 protein, mouse; D054389:Receptors, CCR1; D011994:Recombinant Proteins; D054818:Hexosaminidase A; D054819:Hexosaminidase B; D008359:Mannose-6-Phosphate Isomerase