{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T19:06:22Z","timestamp":1772046382914,"version":"3.50.1"},"reference-count":38,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2010,12,8]],"date-time":"2010-12-08T00:00:00Z","timestamp":1291766400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2011,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective:<\/jats:title><jats:p>Novel recombinant human lysosomal \u03b2\u2010hexosaminidase A (HexA) was developed for enzyme replacement therapy (ERT) for Tay\u2010Sachs and Sandhoff diseases, ie, autosomal recessive GM2 gangliosidoses, caused by HexA deficiency.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods:<\/jats:title><jats:p>A recombinant human HexA (<jats:italic>Om4<\/jats:italic>HexA) with a high mannose 6\u2010phosphate (M6P)\u2010type\u2010N\u2010glycan content, which was produced by a methylotrophic yeast strain, <jats:italic>Ogataea minuta<\/jats:italic>, overexpressing the <jats:italic>OmMNN4<\/jats:italic> gene, was intracerebroventricularly (ICV) administered to Sandhoff disease model mice (<jats:italic>Hexb<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice) at different doses (0.5\u20132.5mg\/kg), and then the replacement and therapeutic effects were examined.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results:<\/jats:title><jats:p>The <jats:italic>Om4<\/jats:italic>HexA was widely distributed across the ependymal cell layer, dose\u2010dependently restored the enzyme activity due to uptake via cell surface cation\u2010independent M6P receptor (CI\u2010M6PR) on neural cells, and reduced substrates, including GM2 ganglioside (GM2), asialo GM2 (GA2), and oligosaccharides with terminal N\u2010acetylglucosamine residues (GlcNAc\u2010oligosaccharides), accumulated in brain parenchyma. A significant inhibition of chemokine macrophage inflammatory protein\u20101 \u03b1 (MIP\u20101\u03b1) induction was also revealed, especially in the hindbrain (&lt;63%). The decrease in central neural storage correlated with an improvement of motor dysfunction as well as prolongation of the lifespan.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation:<\/jats:title><jats:p>This lysosome\u2010directed 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\u2010directed enzyme replacement therapy (NCDERT) for neurodegenerative metabolic diseases. 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