Human recombinant lysosomal β-Hexosaminidases produced in Pichia pastoris efficiently reduced lipid accumulation in Tay-Sachs fibroblasts.
GM2 gangliosidosis
Pichia pastoris
enzyme replacement therapy
recombinant hexosaminidases
Journal
American journal of medical genetics. Part C, Seminars in medical genetics
ISSN: 1552-4876
Titre abrégé: Am J Med Genet C Semin Med Genet
Pays: United States
ID NLM: 101235745
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
13
07
2020
revised:
28
09
2020
accepted:
08
10
2020
pubmed:
29
10
2020
medline:
18
9
2021
entrez:
28
10
2020
Statut:
ppublish
Résumé
GM2 gangliosidosis, Tay-Sachs and Sandhoff diseases, are lysosomal storage disorders characterized by the lysosomal accumulation of GM2 gangliosides. This accumulation is due to deficiency in the activity of the β-hexosaminidases Hex-A or Hex-B, which are dimeric hydrolases formed by αβ or ββ 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 β-hexosaminidases (rhHex-A and rhHex-B) in the methylotrophic yeast Pichia pastoris. In this study, we evaluated in vitro the cellular uptake, intracellular delivery to lysosome, and reduction of stored substrates. Both enzymes were taken-up via endocytic pathway mediated by mannose and mannose-6-phosphate receptors and delivered to lysosomes. Noteworthy, rhHex-A diminished the levels of stored lipids and lysosome mass in fibroblasts from Tay-Sachs patients. Overall, these results confirm the potential of P. pastoris as host to produce recombinant β-hexosaminidases intended to be used in the treatment of GM2 gangliosidosis.
Identifiants
pubmed: 33111489
doi: 10.1002/ajmg.c.31849
pmc: PMC8045741
mid: NIHMS1685281
doi:
Substances chimiques
Hexosaminidases
EC 3.2.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
885-895Subventions
Organisme : Intramural NIH HHS
ID : ZIA TR000018
Pays : United States
Informations de copyright
© 2020 Wiley Periodicals LLC.
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