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

摘要

Classical homocystinuria (HCU) is an inborn error of sulfur amino acidmetabolism caused by deficient activity of cystathionine beta-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 truncatedCBS (PEG-CBS). Full survival of the treatedKOmice, 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 andmitochondria. Furthermore, treatment of the KO mice for 5mo 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-CBSmay prevent clinical symptoms of the disease possibly without the need of dietary protein restriction.