HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Highly phosphomannosylated enzyme replacement therapy for GM2 gangliosidosis.

AbstractOBJECTIVE:
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.
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.
AuthorsDaisuke Tsuji, Hiromi Akeboshi, Kazuhiko Matsuoka, Hiroko Yasuoka, Eri Miyasaki, Yoshiko Kasahara, Ikuo Kawashima, Yasunori Chiba, Yoshifumi Jigami, Takao Taki, Hitoshi Sakuraba, Kohji Itoh
JournalAnnals of neurology (Ann Neurol) Vol. 69 Issue 4 Pg. 691-701 (Apr 2011) ISSN: 1531-8249 [Electronic] United States
PMID21520232 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2010 American Neurological Association.
Chemical References
  • Ccr1 protein, mouse
  • Receptors, CCR1
  • Recombinant Proteins
  • Hexosaminidase A
  • Hexosaminidase B
  • Mannose-6-Phosphate Isomerase
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

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: