Ancestral lysosomal enzymes with increased activity harbor therapeutic potential for treatment of Hunter syndrome
Natalie M. Hendrikse,
Anna Sandegren,
Tommy Andersson,
Jenny Blomqvist,
Åsa Makower,
Dominik Possner,
Chao Su,
Niklas Thalén,
Agneta Tjernberg,
Ulrica Westermark,
Johan Rockberg,
Stefan Svensson Gelius,
Per-Olof Syrén,
Erik Nordling
Affiliations
Natalie M. Hendrikse
Swedish Orphan Biovitrum AB, Stockholm 112 76, Sweden; Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Solna 171 21, Sweden; Department of Fibre and Polymer Technology, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Stockholm 100 44, Sweden
Anna Sandegren
Swedish Orphan Biovitrum AB, Stockholm 112 76, Sweden
Tommy Andersson
Swedish Orphan Biovitrum AB, Stockholm 112 76, Sweden
Jenny Blomqvist
Swedish Orphan Biovitrum AB, Stockholm 112 76, Sweden
Åsa Makower
Swedish Orphan Biovitrum AB, Stockholm 112 76, Sweden
Dominik Possner
Swedish Orphan Biovitrum AB, Stockholm 112 76, Sweden
Chao Su
Swedish Orphan Biovitrum AB, Stockholm 112 76, Sweden
Niklas Thalén
Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Stockholm 10691, Sweden
Agneta Tjernberg
Swedish Orphan Biovitrum AB, Stockholm 112 76, Sweden
Ulrica Westermark
Swedish Orphan Biovitrum AB, Stockholm 112 76, Sweden
Johan Rockberg
Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Stockholm 10691, Sweden
Stefan Svensson Gelius
Swedish Orphan Biovitrum AB, Stockholm 112 76, Sweden
Per-Olof Syrén
Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Solna 171 21, Sweden; Department of Fibre and Polymer Technology, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Stockholm 100 44, Sweden; Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Stockholm 10691, Sweden; Corresponding author
Erik Nordling
Swedish Orphan Biovitrum AB, Stockholm 112 76, Sweden; Corresponding author
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.
