Enzyme Replacement Therapy Ameliorates Multiple Symptoms of Murine Homocystinuria

Classical homocystinuria (HCU) is the most common inherited
disorder of sulfur amino acid metabolism caused by deficiency
in cystathionine beta-synthase (CBS) activity and characterized
by severe elevation of homocysteine in blood and tissues. Treatment
with dietary methionine restriction is not optimal, and
poor compliance leads to serious complications. We developed
an enzyme replacement therapy (ERT) and studied its efficacy
in a severe form of HCU in mouse (the I278T model). Treatment
was initiated before or after the onset of clinical symptoms
in an effort to prevent or reverse the phenotype. ERT
substantially reduced and sustained plasma homocysteine concentration
at around 100 mM and normalized plasma cysteine
for up to 9 months of treatment. Biochemical balance was
also restored in the liver, kidney, and brain. Furthermore,
ERT corrected liver glucose and lipid metabolism. The treatment
prevented or reversed facial alopecia, fragile and lean
phenotype, and low bone mass. In addition, structurally defective
ciliary zonules in the eyes of I278T mice contained low density
and/or broken fibers, while administration of ERT from
birth partially rescued the ocular phenotype. In conclusion,
ERT maintained an improved metabolic pattern and ameliorated
many of the clinical complications in the I278T mouse
model of HCU.