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This accumulation is due to deficiency in the activity of the \u03b2\u2010hexosaminidases Hex\u2010A or Hex\u2010B, which are dimeric hydrolases formed by \u03b1\u03b2 or \u03b2\u03b2 subunits, respectively. These disorders show similar clinical manifestations that range from mild systemic symptoms to neurological damage and premature death. There is still no effective therapy for GM2 gangliosidoses, but some therapeutic alternatives, as enzyme replacement therapy, have being evaluated. Previously, we reported the production of active human recombinant \u03b2\u2010hexosaminidases (rhHex\u2010A and rhHex\u2010B) in the methylotrophic yeast <jats:italic>Pichia pastoris<\/jats:italic>. In this study, we evaluated in vitro the cellular uptake, intracellular delivery to lysosome, and reduction of stored substrates. Both enzymes were taken\u2010up via endocytic pathway mediated by mannose and mannose\u20106\u2010phosphate receptors and delivered to lysosomes. Noteworthy, rhHex\u2010A diminished the levels of stored lipids and lysosome mass in fibroblasts from Tay\u2010Sachs patients. Overall, these results confirm the potential of <jats:italic>P. pastoris<\/jats:italic> as host to produce recombinant \u03b2\u2010hexosaminidases intended to be used in the treatment of GM2 gangliosidosis.<\/jats:p>","DOI":"10.1002\/ajmg.c.31849","type":"journal-article","created":{"date-parts":[[2020,10,28]],"date-time":"2020-10-28T07:18:53Z","timestamp":1603869533000},"page":"885-895","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Human recombinant lysosomal <scp>\u03b2\u2010Hexosaminidases<\/scp> produced in <scp><i>Pichia pastoris<\/i><\/scp> efficiently reduced lipid accumulation in <scp>Tay\u2010Sachs<\/scp> fibroblasts"],"prefix":"10.1002","volume":"184","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9670-6435","authenticated-orcid":false,"given":"Angela J.","family":"Espejo\u2010Mojica","sequence":"first","affiliation":[{"name":"Institute for the Study of Inborn Errors of Metabolism Faculty of Science, Pontificia Universidad Javeriana  Bogot\u00e1 Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5409-3466","authenticated-orcid":false,"given":"Alexander","family":"Rodr\u00edguez\u2010L\u00f3pez","sequence":"additional","affiliation":[{"name":"Institute for the Study of Inborn Errors of Metabolism Faculty of Science, Pontificia Universidad Javeriana  Bogot\u00e1 Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Li","sequence":"additional","affiliation":[{"name":"National Center for Advancing Translational Sciences National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1034-0757","authenticated-orcid":false,"given":"Wei","family":"Zheng","sequence":"additional","affiliation":[{"name":"National Center for Advancing Translational Sciences National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6484-1173","authenticated-orcid":false,"given":"Carlos J.","family":"Alm\u00e9ciga\u2010D\u00edaz","sequence":"additional","affiliation":[{"name":"Institute for the Study of Inborn Errors of Metabolism Faculty of Science, Pontificia Universidad Javeriana  Bogot\u00e1 Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cindy","family":"Dulcey\u2010Sep\u00falveda","sequence":"additional","affiliation":[{"name":"Department of Mathematics, Faculty of Science Pontificia Universidad Javeriana  Bogot\u00e1 Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1878-665X","authenticated-orcid":false,"given":"Germ\u00e1n","family":"Combariza","sequence":"additional","affiliation":[{"name":"Department of Mathematics, Faculty of Science Pontificia Universidad Javeriana  Bogot\u00e1 Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8287-0197","authenticated-orcid":false,"given":"Luis A.","family":"Barrera","sequence":"additional","affiliation":[{"name":"Institute for the Study of Inborn Errors of Metabolism Faculty of Science, Pontificia Universidad Javeriana  Bogot\u00e1 Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,10,27]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1128\/AEM.00463-07"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-55136-4"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2008.10.016"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-013118-111518"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.2174\/1566523218666180404162622"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1005805"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1006\/prep.2000.1325"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/glycob\/cwf096"},{"issue":"9","key":"e_1_2_9_10_1","first-page":"1786","article-title":"Laboratory scale production of the human recombinant iduronate 2\u2010sulfate sulfatase\u2010like from Pichia pastoris","volume":"8","author":"C\u00f3rdoba\u2010Ruiz H. 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