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  • Thalén, NiklasKTH,Proteinteknologi (author)

Tuning of CHO secretional machinery improve activity of secreted therapeutic sulfatase 150-fold

  • Article/chapterEnglish2024

Publisher, publication year, extent ...

  • Elsevier BV,2024
  • printrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:kth-341758
  • https://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-341758URI
  • https://doi.org/10.1016/j.ymben.2023.12.003DOI

Supplementary language notes

  • Language:English
  • Summary in:English

Part of subdatabase

Classification

  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • QC 20240102
  • Rare diseases are, despite their name, collectively common and millions of people are affected daily of conditions where treatment often is unavailable. Sulfatases are a large family of activating enzymes related to several of these diseases. Heritable genetic variations in sulfatases may lead to impaired activity and a reduced macromolecular breakdown within the lysosome, with several severe and lethal conditions as a consequence. While therapeutic options are scarce, treatment for some sulfatase deficiencies by recombinant enzyme replacement are available. The recombinant production of such sulfatases suffers greatly from both low product activity and yield, further limiting accessibility for patient groups. To mitigate the low product activity, we have investigated cellular properties through computational evaluation of cultures with varying media conditions and comparison of two CHO clones with different levels of one active sulfatase variant. Transcriptome analysis identified 18 genes in secretory pathways correlating with increased sulfatase production. Experimental validation by upregulation of a set of three key genes improved the specific enzymatic activity at varying degree up to 150-fold in another sulfatase variant, broadcasting general production benefits. We also identified a correlation between product mRNA levels and sulfatase activity that generated an increase in sulfatase activity when expressed with a weaker promoter. Furthermore, we suggest that our proposed workflow for resolving bottlenecks in cellular machineries, to be useful for improvements of cell factories for other biologics as well.

Subject headings and genre

Added entries (persons, corporate bodies, meetings, titles ...)

  • Moradi, MonaKTH,Proteinteknologi(Swepub:kth)u1b2x5ha (author)
  • Lundqvist, MagnusKTH,Proteinteknologi(Swepub:kth)u1hfekeg (author)
  • Rodhe, JohannaSOBI AB, Tomtebodavagen 23A, Stockholm, Sweden, Tomtebodavägen 23A (author)
  • Andersson, MonicaSOBI AB, Tomtebodavagen 23A, Stockholm, Sweden, Tomtebodavägen 23A (author)
  • Bidkhori, GholamrezaKTH,Science for Life Laboratory, SciLifeLab,Systembiologi,AIVIVO Ltd. Unit 25, Bio-innovation centre, Cambridge Science park, Cambridge, UK, Cambridge Science park(Swepub:kth)u1borjet (author)
  • Possner, DominikSOBI AB, Tomtebodavagen 23A, Stockholm, Sweden, Tomtebodavägen 23A (author)
  • Su, ChaoSOBI AB, Tomtebodavagen 23A, Stockholm, Sweden, Tomtebodavägen 23A (author)
  • Nilsson, JoakimSOBI AB, Tomtebodavagen 23A, Stockholm, Sweden, Tomtebodavägen 23A (author)
  • Eisenhut, PeterACIB - Austrian Centre of Industrial Biotechnology, Krenngasse 37, 8010 Graz, Austria, Krenngasse 37; BOKU - University of Natural Resources and Life Sciences, Department of Biotechnology, Vienna, 1190, Austria (author)
  • Malm, Magdalena,1983-KTH,Proteinteknologi(Swepub:kth)u1cmkpee (author)
  • Karlsson, AliceKTH,Proteinteknologi(Swepub:kth)u1uichw7 (author)
  • Vestin, JeanetteSOBI AB, Tomtebodavagen 23A, Stockholm, Sweden, Tomtebodavägen 23A (author)
  • Forsberg, JohanSOBI AB, Tomtebodavagen 23A, Stockholm, Sweden, Tomtebodavägen 23A (author)
  • Nordling, ErikSOBI AB, Tomtebodavagen 23A, Stockholm, Sweden, Tomtebodavägen 23A (author)
  • Mardinoglu, AdilKTH,Science for Life Laboratory, SciLifeLab,Systembiologi(Swepub:kth)u1t8kmr6 (author)
  • Volk, Anna-LuisaKTH,Proteinteknologi(Swepub:kth)u1j049o2 (author)
  • Sandegren, AnnaSOBI AB, Tomtebodavagen 23A, Stockholm, Sweden, Tomtebodavägen 23A (author)
  • Rockberg, JohanKTH,Proteinteknologi(Swepub:kth)u130jo0a (author)
  • KTHProteinteknologi (creator_code:org_t)

Related titles

  • In:Metabolic engineering: Elsevier BV81, s. 157-1661096-71761096-7184

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