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      Enzyme replacement prevents neonatal death, liver damage, and osteoporosis in murine homocystinuria

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          Abstract

          Classical homocystinuria (HCU) is an inborn error of sulfur amino acid metabolism caused by deficient activity of cystathionine β-synthase (CBS), resulting in an accumulation of homocysteine and a concomitant decrease of cystathionine and cysteine in blood and tissues. In mice, the complete lack of CBS is neonatally lethal. In this study, newborn CBS-knockout (KO) mice were treated with recombinant polyethyleneglycolylated human truncated CBS (PEG-CBS). Full survival of the treated KO mice, along with a positive impact on metabolite levels in plasma, liver, brain, and kidneys, was observed. The PEG-CBS treatment prevented an otherwise fatal liver disease characterized by steatosis, death of hepatocytes, and ultrastructural abnormalities of endoplasmic reticulum and mitochondria. Furthermore, treatment of the KO mice for 5 mo maintained the plasma metabolite balance and completely prevented osteoporosis and changes in body composition that characterize both the KO model and human patients. These findings argue that early treatment of patients with HCU with PEG-CBS may prevent clinical symptoms of the disease possibly without the need of dietary protein restriction.—Majtan, T., Hůlková, H., Park, I., Krijt, J., Kožich, V., Bublil, E. M., Kraus, J. P. Enzyme replacement prevents neonatal death, liver damage, and osteoporosis in murine homocystinuria.

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          Author and article information

          Journal
          FASEB J
          FASEB J
          fasebj
          fasebj
          FASEB
          The FASEB Journal
          Federation of American Societies for Experimental Biology (Bethesda, MD, USA )
          0892-6638
          1530-6860
          December 2017
          16 August 2017
          1 December 2018
          : 31
          : 12
          : 5495-5506
          Affiliations
          [* ]Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA;
          []Institute of Inherited Metabolic Disorders, Charles University-First Faculty of Medicine and General University Hospital, Prague, Czech Republic;
          []Institute of Pathology, Charles University–First Faculty of Medicine and General University Hospital, Prague, Czech Republic; and
          [§ ]Orphan Technologies Limited, Rapperswil, Switzerland
          Author notes
          [1 ]Correspondence: University of Colorado, School of Medicine, 12800 E 19th Ave., Mail Stop 8313, Aurora, CO 80045, USA. E-mail: tomas.majtan@ 123456ucdenver.edu
          [2 ]Correspondence: University of Colorado, School of Medicine, 12800 E 19th Avenue, Mail Stop 8313, Aurora, CO 80045, USA. E-mail: jan.kraus@ 123456ucdenver.edu
          Article
          PMC5690381 PMC5690381 5690381 FJ_201700565R
          10.1096/fj.201700565R
          5690381
          28821635
          acbb6a60-0d35-4b77-a184-b4b7b5f8b8c0
          © FASEB
          History
          : 19 June 2017
          : 31 July 2017
          Page count
          Figures: 7, Tables: 0, Equations: 0, References: 26, Pages: 12
          Categories
          Research
          Custom metadata
          v1

          cystathionine β-synthase,rare inherited disease,preclinical drug development,PEGylation,homocysteine

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