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.