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FASEB J. 2017 Dec;31(12):5495-5506. doi: 10.1096/fj.201700565R. Epub 2017 Aug 16.

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

Author information

1
Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA; tomas.majtan@ucdenver.edu.
2
Institute of Inherited Metabolic Disorders, Charles University-First Faculty of Medicine and General University Hospital, Prague, Czech Republic.
3
Institute of Pathology, Charles University-First Faculty of Medicine and General University Hospital, Prague, Czech Republic; and.
4
Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA.
5
Orphan Technologies Limited, Rapperswil, Switzerland.
6
Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA; jan.kraus@ucdenver.edu.

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.

KEYWORDS:

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

PMID:
28821635
PMCID:
PMC5690381
[Available on 2018-12-01]
DOI:
10.1096/fj.201700565R
[Indexed for MEDLINE]

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