Enzyme Replacement Therapy Ameliorates Multiple Symptoms of Murine Homocystinuria

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