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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • Recombinant Proteins
  • Cystathionine beta-Synthase