Journal
HUMAN MUTATION
Volume 41, Issue 9, Pages 1662-1670Publisher
WILEY-HINDAWI
DOI: 10.1002/humu.24072
Keywords
cystathionine beta-synthase; enzyme replacement therapy; histology; homocysteine; liver disease; rare disease
Categories
Funding
- Grantova Agentura Ceske Republiky [GACR-19-08786S]
- Orphan Technologies Ltd. [AWD-111186, AWD182790]
- American Heart Association [16SDG30040000]
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Classical homocystinuria (HCU) is an inborn error of metabolism caused by loss of cystathionine beta-synthase (CBS) activity with the concomitant buildup of homocysteine. In knockout (KO) mice, a mouse model of HCU, complete lack of CBS is neonatally lethal. Administration of OT-58, an enzyme therapy for HCU, during the first 5 weeks of life rescued KO mice survival by preventing liver disease. Here, we studied the impact of a long-term uninterrupted OT-58 treatment or its absence beyond the neonatal period on liver pathology and metabolism. Plasma and liver metabolites of KO mice on OT-58 treatment were substantially improved or normalized compared with those receiving vehicle. Increased plasma activities of alanine aminotransferase and aspartate aminotransferase of vehicle-injected KO mice suggested the progression of liver damage with age and lack of treatment. At 3 months of age, liver histology showed no signs of hepatopathy in both vehicle- and OT-58-treated KO mice. However, moderate to severe liver disease, characterized by steatosis, hepatocellular necroses, disorganized endoplasmic reticulum, and swollen mitochondria, developed in 6-month-old vehicle-injected KO mice. KO mice on OT-58 treatment remained asymptomatic and were indistinguishable from age-matched healthy controls. Long-term uninterrupted OT-58 treatment was essential to prevent severe liver disease in the KO mouse model of HCU.
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