Premium
Enzyme replacement prevents neonatal death, liver damage, and osteoporosis in murine homocystinuria
Author(s) -
Majtan Tomas,
Hůlková Helena,
Park Insun,
Krijt Jakub,
Kožich Viktor,
Bublil Erez M.,
Kraus Jan P.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201700565r
Subject(s) - homocystinuria , cystathionine beta synthase , endocrinology , medicine , steatosis , cysteine , chemistry , methionine , biochemistry , enzyme , amino acid
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. FASEB J. 31, 5495–5506 (2017). www.fasebj.org