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

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.

• Authors: Tomas Majtan, Helena Hůlková, Insun Park, Jakub Krijt, Viktor Kožich, Erez M Bublil, Jan P Kraus
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 31 Issue 12 Pg. 5495-5506 (12 2017) ISSN: 1530-6860 [Electronic] United States
• PMID: 28821635 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © FASEB.

Chemical References

• Recombinant Proteins
• Cystathionine beta-Synthase

Topics

• Animals
• Body Composition (drug effects)
• Cystathionine beta-Synthase (genetics, metabolism, therapeutic use)
• Disease Models, Animal
• Fatty Liver (enzymology, prevention & control)
• Female
• Homocystinuria (drug therapy, enzymology, metabolism, pathology)
• Liver (drug effects, enzymology, metabolism, pathology)
• Liver Diseases (enzymology, prevention & control)
• Male
• Mice
• Mice, Knockout
• Osteoporosis (prevention & control)
• Recombinant Proteins (therapeutic use)