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

Hendrikse, NatalieKTH,Ytbehandlingsteknik,Science for Life Laboratory, SciLifeLab,Swedish Orphan Biovitrum AB, S-11276 Stockholm, Sweden. (författare)

QC 20210419
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.

Sandegren, AnnaSwedish Orphan Biovitrum AB, S-11276 Stockholm, Sweden. (författare)
Andersson, TommySwedish Orphan Biovitrum AB, S-11276 Stockholm, Sweden. (författare)
Blomqvist, JennySwedish Orphan Biovitrum AB, S-11276 Stockholm, Sweden. (författare)
Makower, AsaSwedish Orphan Biovitrum AB, S-11276 Stockholm, Sweden. (författare)
Possner, DominikSwedish Orphan Biovitrum AB, S-11276 Stockholm, Sweden. (författare)
Su, ChaoSwedish Orphan Biovitrum AB, S-11276 Stockholm, Sweden. (författare)
Thalén, NiklasKTH,Proteinteknologi(Swepub:kth)u19nerw9 (författare)
Tjernberg, AgnetaSwedish Orphan Biovitrum AB, S-11276 Stockholm, Sweden. (författare)
Westermark, UlricaSwedish Orphan Biovitrum AB, S-11276 Stockholm, Sweden. (författare)
Rockberg, JohanKTH,Proteinteknologi(Swepub:kth)u130jo0a (författare)
Gelius, Stefan SvenssonSwedish Orphan Biovitrum AB, S-11276 Stockholm, Sweden. (författare)
Syrén, Per-OlofKTH,Science for Life Laboratory, SciLifeLab,Ytbehandlingsteknik,Proteinvetenskap(Swepub:kth)u1ewlo1g (författare)
Nordling, ErikSwedish Orphan Biovitrum AB, S-11276 Stockholm, Sweden. (författare)
KTHYtbehandlingsteknik (creator_code:org_t)

Av författaren/redakt...: Hendrikse, Natal ...; Sandegren, Anna; Andersson, Tommy; Blomqvist, Jenny; Makower, Asa; Possner, Dominik; visa fler...; Su, Chao; Thalén, Niklas; Tjernberg, Agnet ...; Westermark, Ulri ...; Rockberg, Johan; Gelius, Stefan S ...; Syrén, Per-Olof; Nordling, Erik; visa färre...

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