Variant, recombinant beta-glucocerebrosidase proteins with increased stability and increased retained catalytic activity

摘要

Described herein are variant, recombinant β-glucocerebrosidase proteins characterized as having increased stability relative to recombinant wild-type β-glucocerebrosidase. Also provided herein are variant, recombinant β-glucocerebrosidase proteins characterized as retaining more catalytic activity relative to recombinant wild-type β-glucocerebrosidase. Further described herein are variant, recombinant β-glucocerebrosidase proteins that can have amino acid variations at one or more of the following positions: 316, 317, 321 and 145. Methods of making the variant, recombinant β-glucocerebrosidase proteins are also described as well as methods of treating patients having lysosomal storage diseases.

主权项

1. A composition comprising:
a variant, recombinant human β-glucocerebrosidase protein, wherein the protein has at least one substitution relative to SEQ ID NO: 1, and wherein the substitution is selected from the group consisting of
F316A relative to SEQ ID NO: 21,L317F relative to SEQ ID NO: 21,K321V relative to SEQ ID NO: 21,K321A relative to SEQ ID NO: 21,H145L relative to SEQ ID NO: 17,H145F relative to SEQ ID NO: 17,and combinations thereof; and isofagomine.