Journal
FASEB JOURNAL
Volume 33, Issue 11, Pages 12477-12486Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.201901203R
Keywords
cystathionine beta-synthase; homocysteine; anxiety; endothelial dysfunction; thrombosis
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Funding
- American Heart Association Scientist Development Grant [16SDG30040000]
- Orphan Technologies, Ltd., a private pharmaceutical company developing an enzyme replacement therapy for cystathionine b-synthase (CBS)-deficient homocystinuria
- U.S. National Institutes of Health, Office of the Director [1S10OD018156-01]
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Classic homocystinuria (HCU) is an inherited disorder characterized by elevated homocysteine (Hcy) in plasma and tissues resulting from cystathionine beta-synthase (CBS) deficiency. There is no cure, and patients are predominantly managed by methionine-restricted diet (MRD) to limit the production of Hcy. In this study, we used the I278T mouse model of HCU to evaluate the long-term impact of a novel enzyme replacement therapy [truncated human CBS C155 mutant modified with linear 20-kDa N-hydroxysuccinimide ester polyethylene glycol OT-58)] on clinical end points relevant to human patients with HCU. In addition, we compared its efficacy on a background of either MRD or normal methionine intake [regular diet (REG)] to that of MRD alone. We found that, compared with untreated I278T mice, OT-58 treatment of I278T mice fed with the REG diet resulted in a 90% decrease in plasma Hcy concentrations and correction of learning/cognition, endothelial dysfunction, hemostasis, bone mineralization, and body composition. On background of the MRD, OT-58 performed equally well with plasma Hcy entirely normalized. The MRD alone decreased plasma Hcy by 67% and corrected the HCU phenotype in I278T mice. However, the MRD increased anxiety and reduced bone mineral content in both I278T mice and wild-type controls. This study shows that OT-58 is a highly efficacious novel treatment for HCU on the background of either normal or restricted methionine intake.
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