Abstract | OBJECTIVE: 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. INTERPRETATION:
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Authors | Daisuke Tsuji, Hiromi Akeboshi, Kazuhiko Matsuoka, Hiroko Yasuoka, Eri Miyasaki, Yoshiko Kasahara, Ikuo Kawashima, Yasunori Chiba, Yoshifumi Jigami, Takao Taki, Hitoshi Sakuraba, Kohji Itoh |
Journal | Annals of neurology
(Ann Neurol)
Vol. 69
Issue 4
Pg. 691-701
(Apr 2011)
ISSN: 1531-8249 [Electronic] United States |
PMID | 21520232
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2010 American Neurological Association. |
Chemical References |
- Ccr1 protein, mouse
- Receptors, CCR1
- Recombinant Proteins
- Hexosaminidase A
- Hexosaminidase B
- Mannose-6-Phosphate Isomerase
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Topics |
- Animals
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Enzyme Replacement Therapy
(methods)
- Gangliosidoses, GM2
(drug therapy, enzymology, genetics, pathology)
- Hexosaminidase A
(administration & dosage, genetics)
- Hexosaminidase B
(genetics)
- Humans
- Injections, Intraventricular
- Lysosomes
(enzymology)
- Mannose-6-Phosphate Isomerase
(administration & dosage)
- Mice
- Mice, Knockout
- Receptors, CCR1
(antagonists & inhibitors)
- Recombinant Proteins
- Sandhoff Disease
(drug therapy, enzymology)
- Tay-Sachs Disease
(drug therapy, genetics)
- Treatment Outcome
- Yeasts
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