Ancestral lysosomal enzymes with increased activity harbor therapeutic potential for treatment of Hunter syndrome

iScience

Tommy Andersson¹  Anna Sandegren²  Ulrica Westermark³  Per-Olof Syrén³  Dominik Possner⁴  Niklas Thalén⁴  Agneta Tjernberg⁴  Jenny Blomqvist⁴  Chao Su⁴  Åsa Makower⁴  Stefan Svensson Gelius⁴  Erik Nordling⁴  Johan Rockberg⁴  Natalie M. Hendrikse⁴ 

[1] Department of Fibre and Polymer Technology, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Stockholm 100 44, 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 Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Stockholm 10691, Sweden;Swedish Orphan Biovitrum AB, Stockholm 112 76, Sweden;

关键词: Biochemistry;    Structural Biology;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown