Enzyme replacement with PEGylated cystathionine β-synthase ameliorates homocystinuria in murine model
Erez M. Bublil, … , Viktor Kožich, Jan P. Kraus
Erez M. Bublil, … , Viktor Kožich, Jan P. Kraus
Published May 16, 2016
Citation Information: J Clin Invest. 2016;126(6):2372-2384. https://doi.org/10.1172/JCI85396.
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Research Article Genetics Metabolism

Enzyme replacement with PEGylated cystathionine β-synthase ameliorates homocystinuria in murine model

Abstract

Homocystinuria, which typically results from cystathionine β-synthase (CBS) deficiency, is the most common defect of sulfur amino acid metabolism. CBS condenses homocysteine and serine to cystathionine that is then converted to cysteine. Individuals with homocystinuria have markedly elevated plasma levels of homocysteine and methionine and reduced concentrations of cystathionine and cysteine. Clinical disease manifestations include thromboembolism and neuropsychiatric, ocular, and skeletal complications. Here, we have shown that administration of PEGylated CBS into the circulation of homocystinuria model mice alters the extra- and intracellular equilibrium of sulfur amino acids, resulting in a decrease of approximately 75% in plasma total homocysteine (tHcy) and normalization of cysteine concentrations. Moreover, the decrease in homocysteine and the normalization of cysteine in PEGylated CBS–treated model mice were accompanied by improvement of histopathological liver symptoms and increased survival. Together, these data suggest that CBS enzyme replacement therapy (ERT) is a promising approach for the treatment of homocystinuria and that ERT for metabolic diseases may not necessitate introduction of the deficient enzyme into its natural intracellular compartment.

Authors

Erez M. Bublil, Tomas Majtan, Insun Park, Richard S. Carrillo, Helena Hůlková, Jakub Krijt, Viktor Kožich, Jan P. Kraus

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Figure 3

Repeated injection of PEGhtCBS significantly impacts tHcy, cystathionine, and cysteine plasma levels.

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Repeated injection of PEGhtCBS significantly impacts tHcy, cystathionine...
(A) Metabolites levels in HO mice (n = 6) throughout a 24-hour cycle. (B) tHcy levels in individual HO mice (n = 6) that were injected with 5 mg/kg PEGhtCBS for 5 consecutive days on weeks 1 and 3. (C) Mean tHcy and cystathionine levels of the animals described in B. See Figure 4 for typical levels of metabolites in untreated HO mice. (D) Mean tHcy and cystathionine levels in HO mice (n = 5) that were injected with 5 mg/kg non-PEGylated htCBS for 5 consecutive days on weeks 1 and 3. (E) Comparison of cysteine levels in the animals injected with PEGylated versus non-PEGylated htCBS. Data in A, C, and D are presented as the mean ± SEM and are compared with time 0 values, using a paired Student’s t test. Data in E are presented as the mean ± SEM, and each time point is compared between the 2 groups using an unpaired Student’s t test. *P ≤ 0.05, **P ≤ 0.01, and ***P ≤ 0.001. Arrows in panels B–E represent injection times.