Abstract:
:Lysosomal storage diseases are treated with human lysosomal enzymes produced in mammalian cells. Such enzyme therapeutics contain relatively low levels of mannose-6-phosphate, which is required to target them to the lysosomes of patient cells. Here we describe a method for increasing mannose-6-phosphate modification of lysosomal enzymes produced in yeast. We identified a glycosidase from C. cellulans that 'uncaps' N-glycans modified by yeast-type mannose-Pi-6-mannose to generate mammalian-type N-glycans with a mannose-6-phosphate substitution. Determination of the crystal structure of this glycosidase provided insight into its substrate specificity. We used this uncapping enzyme together with α-mannosidase to produce in yeast a form of the Pompe disease enzyme α-glucosidase rich in mannose-6-phosphate. Compared with the currently used therapeutic version, this form of α-glucosidase was more efficiently taken up by fibroblasts from Pompe disease patients, and it more effectively reduced cardiac muscular glycogen storage in a mouse model of the disease.
journal_name
Nat Biotechnoljournal_title
Nature biotechnologyauthors
Tiels P,Baranova E,Piens K,De Visscher C,Pynaert G,Nerinckx W,Stout J,Fudalej F,Hulpiau P,Tännler S,Geysens S,Van Hecke A,Valevska A,Vervecken W,Remaut H,Callewaert Ndoi
10.1038/nbt.2427subject
Has Abstractpub_date
2012-12-01 00:00:00pages
1225-31issue
12eissn
1087-0156issn
1546-1696pii
nbt.2427journal_volume
30pub_type
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