Ancestral lysosomal enzymes with increased activity harbor therapeutic potential for treatment of Hunter syndrome
| Autor: | Åsa Makower, Anna Sandegren, Per-Olof Syrén, Stefan Svensson Gelius, Chao Su, Natalie M. Hendrikse, Dominik Possner, Agneta Tjernberg, Tommy Andersson, Niklas Thalén, Johan Rockberg, Jenny Blomqvist, Erik Nordling, Ulrica Westermark |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
02 engineering and technology Biology Bioinformatics Biochemistry Article law.invention 03 medical and health sciences law Structural Biology medicine Lysosomal storage disease lcsh:Science Receptor chemistry.chemical_classification Multidisciplinary Therapeutic effect Hunter syndrome Enzyme replacement therapy 021001 nanoscience & nanotechnology medicine.disease 030104 developmental biology Enzyme chemistry Recombinant DNA lcsh:Q 0210 nano-technology Function (biology) |
| Zdroj: | iScience iScience, Vol 24, Iss 3, Pp 102154-(2021) |
| ISSN: | 2589-0042 |
| Popis: | Summary We show the successful application of ancestral sequence reconstruction to enhance the activity of iduronate-2-sulfatase (IDS), thereby increasing its therapeutic potential for the treatment of Hunter syndrome—a lysosomal storage disease caused by impaired function of IDS. Current treatment, enzyme replacement therapy with recombinant human IDS, does not alleviate all symptoms, and an unmet medical need remains. We reconstructed putative ancestral sequences of mammalian IDS and compared them with extant IDS. Some ancestral variants displayed up to 2-fold higher activity than human IDS in in vitro assays and cleared more substrate in ex vivo experiments in patient fibroblasts. This could potentially allow for lower dosage or enhanced therapeutic effect in enzyme replacement therapy, thereby improving treatment outcomes and cost efficiency, as well as reducing treatment burden. In summary, we showed that ancestral sequence reconstruction can be applied to lysosomal enzymes that function in concert with modern enzymes and receptors in cells. Graphical abstract Highlights • Reconstruction of ancestral lysosomal enzymes that function in complex cellular context • Ancestral iduronate-2-sulfatases with increased activity compared with the human enzyme • Increased clearance of substrate in patient fibroblasts indicates therapeutic potential Biochemistry; Structural Biology |
| Databáze: | OpenAIRE |
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