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

Classical homocystinuria (HCU) is an inborn error of sulfur amino acidmetabolism caused by deficient

activity of cystathionine b-synthase (CBS), resulting in an accumulation of homocysteine and a concomitant decrease

of cystathionine and cysteine in blood and tissues. Inmice, 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 onmetabolite 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 KOmice for 5mo maintained the plasma metabolite balance and

completely prevented osteoporosis and changes in body composition that characterize both the KO model and

humanpatients. These findings argue that early treatment of patients withHCUwith PEG-CBSmay prevent clinical

symptoms of the disease possibly without the need of dietary protein restriction.