Enzyme replacement prevents neonatal death, liver damage, and osteoporosis in murine homocystinuria

Majtán, Tomáš; Hůlková, Helena; Park, Insun; Krijt, Jakub; Kožich, Viktor; Bublil, Erez M.; Kraus, Jan P.

doi:10.1096/fj.201700565r

Cited by 23 publications

(37 citation statements)

References 26 publications

(52 reference statements)

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“…Long-term treatment with OT-58 resulted in better plasma metabolic balance than Met restriction Dysregulation of sulfur amino acid metabolism is the key feature of HCU phenotype in both human patients and mouse models of the disease. Sustained improvement or restoration of metabolic control are the key aspects of successful treatment (4,10,12). As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Behavior, body composition, and vascular phenotype of homocystinuric mice on methionine‐restricted diet or enzyme replacement therapy

Majtán

Park

Cox³

et al. 2019

FASEB j.

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Classic homocystinuria (HCU) is an inherited disorder characterized by elevated homocysteine (Hcy) in plasma and tissues resulting from cystathionine β‐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 C15S 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.—Majtan, T., Park, I., Cox, A., Branchford, B. R., di Paola, J., Bublil, E. M., Kraus, J. P. Behavior, body composition, and vascular phenotype of homocystinuric mice on methionine‐restricted diet or enzyme replacement therapy. FASEB J. 33, 12477–12486 (2019). http://www.fasebj.org

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Section: Resultsmentioning

confidence: 99%

Behavior, body composition, and vascular phenotype of homocystinuric mice on methionine‐restricted diet or enzyme replacement therapy

Majtán

Park

Cox³

et al. 2019

FASEB j.

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“…We found that a long-term uninterrupted treatment with OT-58 was necessary to prevent onset and development of moderate to severe hepatopathy in KO mice. In addition, comparison of the 3-and 6-month cohorts showed that discontinuation of OT-58 treatment after the initial 5 weeks period to overcome KO mice neonatal lethality (Bublil et al, 2016;Maclean et al, 2010;Majtan, Hulkova, et al, 2017) for 7 weeks (i.e. the 3-month cohort) did not result in immediate discrete and distinguishing changes in liver histology (Figure 4).…”

Section: Discussionmentioning

confidence: 99%

“…Despite restoring fertility and lactation in KO females, addition of 2% betaine or N-acetylcysteine to drinking water had negligible effect on survival of KO pups as well as hepatic injury (Maclean et al, 2010). KO mice also showed decreased bone mineralization and autoimmune disease (Majtan, Hulkova, et al, 2017;Yang et al, 2015). On the contrary, neonatal semilethal phenotype and pronounced liver injury are not observed F I G U R E 5 Histopathological assessment of livers from the 6-month cohort at the light and electron microscopy levels.…”

Section: Discussionmentioning

confidence: 99%

“…Administration of OT-58 to KO pups from Day 2 after birth for 5 weeks resulted in close to 100% survival (Majtan, Hulkova, et al, 2017) and thus allowed, for the first time, long-term studies to be conducted using this mouse model of severe HCU. Subcutaneously administered OT-58 corrected plasma metabolic balance and sustained it over the entire duration of the study (Figure 1).…”

Section: Discussionmentioning

confidence: 99%

“…Quantification of metabolite concentrations was performed in a blinded fashion without knowledge of the animal genotype and/or treatment regimen. Tissue metabolites were determined in homogenates using livers from PBS-perfused mice by high-performance liquid chromatography and LC-MS/MS as described elsewhere (Majtan, Hulkova, et al, 2017). Sulfur metabolites in livers were determined only in 3-month cohort.…”

Section: Determination Of Sulfur Metabolites and Liver Function Marmentioning

confidence: 99%

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Long‐term uninterrupted enzyme replacement therapy prevents liver disease in murine model of severe homocystinuria

et al. 2020

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Classical homocystinuria (HCU) is an inborn error of metabolism caused by loss of cystathionine β‐synthase (CBS) activity with the concomitant buildup of homocysteine. In knockout (KO) mice, a mouse model of HCU, complete lack of CBS is neonatally lethal. Administration of OT‐58, an enzyme therapy for HCU, during the first 5 weeks of life rescued KO mice survival by preventing liver disease. Here, we studied the impact of a long‐term uninterrupted OT‐58 treatment or its absence beyond the neonatal period on liver pathology and metabolism. Plasma and liver metabolites of KO mice on OT‐58 treatment were substantially improved or normalized compared with those receiving vehicle. Increased plasma activities of alanine aminotransferase and aspartate aminotransferase of vehicle‐injected KO mice suggested the progression of liver damage with age and lack of treatment. At 3 months of age, liver histology showed no signs of hepatopathy in both vehicle‐ and OT‐58‐treated KO mice. However, moderate to severe liver disease, characterized by steatosis, hepatocellular necroses, disorganized endoplasmic reticulum, and swollen mitochondria, developed in 6‐month‐old vehicle‐injected KO mice. KO mice on OT‐58 treatment remained asymptomatic and were indistinguishable from age‐matched healthy controls. Long‐term uninterrupted OT‐58 treatment was essential to prevent severe liver disease in the KO mouse model of HCU.

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Cystathionine β‐Synthase ( CBS ) Deficiency: Genetics

Kožich

Kraus

Majtán

2018

Encyclopedia of Life Sciences

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Cystathionine β‐synthase (CBS) catalyses condensation of homocysteine and serine to cystathionine, and by alternative reactions also synthesis of hydrogen sulfide. CBS deficiency, an autosomal recessive trait with estimated worldwide frequency of 0.82–1.09 per 100 000 births, manifests usually by thromboembolism, and in severe forms also by lens dislocation, marfanoid features, osteoporosis and neuropsychiatric complications. Laboratory findings include grossly elevated plasma total homocysteine and mildly to grossly elevated blood methionine, which is analysed in neonatal screening. CBS binds three cofactors: pyridoxal‐5′‐phosphate, an allosteric activator S ‐adenosylmethionine and haem with as‐yet‐unresolved function. In the CBS gene, more than 160 different mutations have been described to date. Most of the mutations are missense yielding misfolded enzymes, which can potentially be rescued by chaperones. CBS deficiency is efficiently treated by combination of large doses of pyridoxine, methionine‐restricted diet and betaine; experimental enzyme replacement therapy is efficient in mouse models of disease. Key Concepts Cystathionine β‐synthase catalyses the first step in the transsulfuration of homocysteine to cysteine, and also synthesis of hydrogen sulfide from cysteine. Cystathionine β‐synthase is a modular enzyme composed of a haem‐binding N ‐terminal domain, the active core with pyridoxal‐5′‐phosphate involved in catalysis and the C ‐terminal autoinhibitory domain, which binds S ‐adenosylmethionine. More than 160 different pathogenic mutations have been described in the CBS gene, almost 90% of all mutant CBS alleles carry missense mutations. Mutant CBS subunits often misfold, and their conformation and activity may be rescued by chaperones. Deficient CBS activity leads to gross elevation of plasma total homocysteine, often to elevated blood methionine levels, and decreased blood cystathionine. Phenotypic consequences of mutations in the Cbs gene include thromboembolism and vascular occlusion, which is accompanied in severe forms of the disease by lens dislocation, marfanoid features, osteoporosis and neuropsychiatric involvement. CBS deficiency can be managed by administration of pyridoxine, low‐methionine diet and betaine; treatment is efficient when started early after birth. Population frequency of patients with CBS deficiency ascertained clinically and by newborn screening is one to two orders of magnitude lower than the frequency calculated from the prevalence of heterozygotes for pathogenic mutations; this observation indicates an ascertainment bias or lack of symptoms in many CBS‐deficient individuals. Various murine models of CBS deficiency recapitulate the organ involvement observed in human patients, and experimental enzyme replacement therapy corrects efficiently these complications.

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Enzyme replacement prevents neonatal death, liver damage, and osteoporosis in murine homocystinuria

Cited by 23 publications

References 26 publications

Behavior, body composition, and vascular phenotype of homocystinuric mice on methionine‐restricted diet or enzyme replacement therapy

Behavior, body composition, and vascular phenotype of homocystinuric mice on methionine‐restricted diet or enzyme replacement therapy

Long‐term uninterrupted enzyme replacement therapy prevents liver disease in murine model of severe homocystinuria

Cystathionine β‐Synthase ( CBS ) Deficiency: Genetics

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