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Publication
Enzyme Replacement Therapy Ameliorates Multiple Symptoms of Murine
Homocystinuria.
Authors Majtan T, Jones W, Krijt J, Park I, Kruger WD, Kožich V, Bassnett S, Bublil EM,
Kraus JP
Submitted By Submitted Externally on 5/25/2018
Status Published
Journal Molecular therapy : the journal of the American Society of Gene Therapy
Year 2018
Date Published 3/1/2018
Volume : Pages 26 : 834 - 844
PubMed Reference 29398487
Abstract 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 µM 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.




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