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J Am Soc Nephrol. 2017 May;28(5):1462-1474. doi: 10.1681/ASN.2015070745. Epub 2016 Dec 8.

Moss-Produced, Glycosylation-Optimized Human Factor H for Therapeutic Application in Complement Disorders.

Author information

1
Department of Pediatrics and Adolescent Medicine, Faculty of Medicine, University of Freiburg Medical Center, Freiburg, Germany.
2
Plant Biotechnology, Faculty of Biology, University of Freiburg, Freiburg, Germany.
3
Greenovation Biotech GmbH, Freiburg, Germany.
4
Leibniz Institute for Natural Product Research and Infection Biology, Friedrich Schiller University, Jena, Germany.
5
BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany; and.
6
FRIAS Freiburg Institute for Advanced Studies, University of Freiburg, Freiburg, Germany.
7
Plant Biotechnology, Faculty of Biology, University of Freiburg, Freiburg, Germany; karsten.haeffner@uniklinik-freiburg.de eva.decker@biologie.uni-freiburg.de.
8
Department of Pediatrics and Adolescent Medicine, Faculty of Medicine, University of Freiburg Medical Center, Freiburg, Germany; karsten.haeffner@uniklinik-freiburg.de eva.decker@biologie.uni-freiburg.de.

Abstract

Genetic defects in complement regulatory proteins can lead to severe renal diseases, including atypical hemolytic uremic syndrome and C3 glomerulopathies, and age-related macular degeneration. The majority of the mutations found in patients with these diseases affect the glycoprotein complement factor H, the main regulator of the alternative pathway of complement activation. Therapeutic options are limited, and novel treatments, specifically those targeting alternative pathway activation, are highly desirable. Substitution with biologically active factor H could potentially treat a variety of diseases that involve increased alternative pathway activation, but no therapeutic factor H is commercially available. We recently reported the expression of full-length recombinant factor H in moss (Physcomitrella patens). Here, we present the production of an improved moss-derived recombinant human factor H devoid of potentially immunogenic plant-specific sugar residues on protein N-glycans, yielding approximately 1 mg purified moss-derived human factor H per liter of initial P. patens culture after a multistep purification process. This glycosylation-optimized factor H showed full in vitro complement regulatory activity similar to that of plasma-derived factor H and efficiently blocked LPS-induced alternative pathway activation and hemolysis induced by sera from patients with atypical hemolytic uremic syndrome. Furthermore, injection of moss-derived factor H reduced C3 deposition and increased serum C3 levels in a murine model of C3 glomerulopathy. Thus, we consider moss-produced recombinant human factor H a promising pharmaceutical product for therapeutic intervention in patients suffering from complement dysregulation.

KEYWORDS:

C3 glomerulopathy; FHmoss; atypical hemolytic uremic syndrome; chronic kidney disease; complement; pediatric nephrology

PMID:
27932477
PMCID:
PMC5407710
DOI:
10.1681/ASN.2015070745
[Indexed for MEDLINE]
Free PMC Article

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