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Majtan T , Jones W Jr , Krijt J , Park I , Kruger WD , Kozich V , Bassnett S , Bublil EM , Kraus JP
Enzyme Replacement Therapy Ameliorates Multiple Symptoms of Murine Homocystinuria
Mol Ther. 2018 Mar 7;26(3) :834-844
PMID: 29398487    PMCID: PMC5910661    URL: https://www.ncbi.nlm.nih.gov/pubmed/29398487
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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 muM 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.
Majtan, Tomas Jones, Wendell Jr. Krijt, Jakub Park, Insun Kruger, Warren D Kozich, Viktor Bassnett, Steven Bublil, Erez M Kraus, Jan P Research Support, N.I.H., Extramural eng Mol Ther. 2018 Mar 7;26(3):834-844. doi: 10.1016/j.ymthe.2017.12.014. Epub 2017 Dec 19.