Biomarkers of oxidative stress, inflammation, and vascular dysfunction in inherited cystathionine β-synthase deficient homocystinuria and the impact of taurine treatment in a phase 1/2 human clinical trial
Corresponding Author
Johan L. K. Van Hove
Department of Pediatrics, School of Medicine, University of Colorado, Aurora, Colorado
Johan L. K. Van Hove and Cynthia L. Freehauf contributed equally to this study.Correspondence
Johan L. K. Van Hove, Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado, Mailstop 8400, Education 2 South, L28-4114, East 17th Avenue, Aurora, CO 80045.
Email: [email protected]
Kenneth N. MacLean, Department of Pediatrics, University of Colorado, School of Medicine, Mailstop 8313, Aurora, CO 80045-0511.
Email: [email protected]
Search for more papers by this authorCynthia L. Freehauf
Department of Pediatrics, School of Medicine, University of Colorado, Aurora, Colorado
Johan L. K. Van Hove and Cynthia L. Freehauf contributed equally to this study.Search for more papers by this authorCan Ficicioglu
Division of Human Genetics, The Children's Hospital Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
Search for more papers by this authorLoren D. M. Pena
Division of Medical Genetics, Department of Pediatrics, Duke University, Durham, North Carolina
Present address Loren D.M. Pena, Division of Human Genetics, Cincinnati Children's Hospital and Medical Center, and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.Search for more papers by this authorKerrie L. Moreau
Department of Medicine, School of Medicine, University of Colorado, Aurora, Colorado
Geriatric Research and Education Center, Denver Veterans Administration Medical Center, Aurora, Colorado
Search for more papers by this authorThomas K. Henthorn
iC42 Clinical Research and Development, Department of Anesthesiology, School of Medicine, University of Colorado, Aurora, Colorado
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado
Search for more papers by this authorUwe Christians
iC42 Clinical Research and Development, Department of Anesthesiology, School of Medicine, University of Colorado, Aurora, Colorado
Search for more papers by this authorHua Jiang
Department of Pediatrics, School of Medicine, University of Colorado, Aurora, Colorado
Search for more papers by this authorTina M. Cowan
Department of Pathology, Stanford University, Stanford, California
Search for more papers by this authorSarah P. Young
Division of Medical Genetics, Department of Pediatrics, Duke University, Durham, North Carolina
Search for more papers by this authorMichelle Hite
Research Institute, Children's Hospital Colorado, Aurora, Colorado
Search for more papers by this authorMarisa W. Friederich
Department of Pediatrics, School of Medicine, University of Colorado, Aurora, Colorado
Search for more papers by this authorSally P. Stabler
Department of Medicine, School of Medicine, University of Colorado, Aurora, Colorado
Search for more papers by this authorElaine B. Spector
Department of Pediatrics, School of Medicine, University of Colorado, Aurora, Colorado
Search for more papers by this authorKathryn E. Kronquist
Department of Pediatrics, School of Medicine, University of Colorado, Aurora, Colorado
Search for more papers by this authorJanet A. Thomas
Department of Pediatrics, School of Medicine, University of Colorado, Aurora, Colorado
Search for more papers by this authorPeggy Emmett
CTRC Core Laboratory, Children's Hospital Colorado, Aurora, Colorado
Search for more papers by this authorMary J. Harrington
CTRC Core Laboratory, Children's Hospital Colorado, Aurora, Colorado
Search for more papers by this authorLaura Pyle
Department of Pediatrics, School of Medicine, University of Colorado, Aurora, Colorado
Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado, Aurora, Colorado
Search for more papers by this authorGeralyn Creadon-Swindell
Department of Pediatrics, School of Medicine, University of Colorado, Aurora, Colorado
Search for more papers by this authorMichael F. Wempe
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado
Search for more papers by this authorKenneth N. MacLean
Department of Pediatrics, School of Medicine, University of Colorado, Aurora, Colorado
Search for more papers by this authorCorresponding Author
Johan L. K. Van Hove
Department of Pediatrics, School of Medicine, University of Colorado, Aurora, Colorado
Johan L. K. Van Hove and Cynthia L. Freehauf contributed equally to this study.Correspondence
Johan L. K. Van Hove, Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado, Mailstop 8400, Education 2 South, L28-4114, East 17th Avenue, Aurora, CO 80045.
Email: [email protected]
Kenneth N. MacLean, Department of Pediatrics, University of Colorado, School of Medicine, Mailstop 8313, Aurora, CO 80045-0511.
Email: [email protected]
Search for more papers by this authorCynthia L. Freehauf
Department of Pediatrics, School of Medicine, University of Colorado, Aurora, Colorado
Johan L. K. Van Hove and Cynthia L. Freehauf contributed equally to this study.Search for more papers by this authorCan Ficicioglu
Division of Human Genetics, The Children's Hospital Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
Search for more papers by this authorLoren D. M. Pena
Division of Medical Genetics, Department of Pediatrics, Duke University, Durham, North Carolina
Present address Loren D.M. Pena, Division of Human Genetics, Cincinnati Children's Hospital and Medical Center, and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.Search for more papers by this authorKerrie L. Moreau
Department of Medicine, School of Medicine, University of Colorado, Aurora, Colorado
Geriatric Research and Education Center, Denver Veterans Administration Medical Center, Aurora, Colorado
Search for more papers by this authorThomas K. Henthorn
iC42 Clinical Research and Development, Department of Anesthesiology, School of Medicine, University of Colorado, Aurora, Colorado
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado
Search for more papers by this authorUwe Christians
iC42 Clinical Research and Development, Department of Anesthesiology, School of Medicine, University of Colorado, Aurora, Colorado
Search for more papers by this authorHua Jiang
Department of Pediatrics, School of Medicine, University of Colorado, Aurora, Colorado
Search for more papers by this authorTina M. Cowan
Department of Pathology, Stanford University, Stanford, California
Search for more papers by this authorSarah P. Young
Division of Medical Genetics, Department of Pediatrics, Duke University, Durham, North Carolina
Search for more papers by this authorMichelle Hite
Research Institute, Children's Hospital Colorado, Aurora, Colorado
Search for more papers by this authorMarisa W. Friederich
Department of Pediatrics, School of Medicine, University of Colorado, Aurora, Colorado
Search for more papers by this authorSally P. Stabler
Department of Medicine, School of Medicine, University of Colorado, Aurora, Colorado
Search for more papers by this authorElaine B. Spector
Department of Pediatrics, School of Medicine, University of Colorado, Aurora, Colorado
Search for more papers by this authorKathryn E. Kronquist
Department of Pediatrics, School of Medicine, University of Colorado, Aurora, Colorado
Search for more papers by this authorJanet A. Thomas
Department of Pediatrics, School of Medicine, University of Colorado, Aurora, Colorado
Search for more papers by this authorPeggy Emmett
CTRC Core Laboratory, Children's Hospital Colorado, Aurora, Colorado
Search for more papers by this authorMary J. Harrington
CTRC Core Laboratory, Children's Hospital Colorado, Aurora, Colorado
Search for more papers by this authorLaura Pyle
Department of Pediatrics, School of Medicine, University of Colorado, Aurora, Colorado
Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado, Aurora, Colorado
Search for more papers by this authorGeralyn Creadon-Swindell
Department of Pediatrics, School of Medicine, University of Colorado, Aurora, Colorado
Search for more papers by this authorMichael F. Wempe
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado
Search for more papers by this authorKenneth N. MacLean
Department of Pediatrics, School of Medicine, University of Colorado, Aurora, Colorado
Search for more papers by this authorFunding information: Children's Hospital Colorado Research Institute; National Center for Advancing Translational Sciences, Grant/Award Number: UL1 TR002535; U.S. Food and Drug Administration, Grant/Award Number: 1R01 FD003907-01A3; Walter S. and Lucienne Driskill Foundation; William R. Hummel Homocystinuria Research Fund
Abstract
Study Objective
A phase 1/2 clinical trial was performed in individuals with cystathionine β synthase (CBS) deficient homocystinuria with aims to: (a) assess pharmacokinetics and safety of taurine therapy, (b) evaluate oxidative stress, inflammation, and vascular function in CBS deficiency, and (c) evaluate the impact of short-term taurine treatment.
Methods
Individuals with pyridoxine-nonresponsive CBS deficiency with homocysteine >50 μM, without inflammatory disorder or on antioxidant therapy were enrolled. Biomarkers of oxidative stress and inflammation, endothelial function (brachial artery flow-mediated dilation [FMD]), and disease-related metabolites obtained at baseline were compared to normal values. While maintaining current treatment, patients were treated with 75 mg/kg taurine twice daily, and treatment response assessed after 4 hours and 4 days.
Results
Fourteen patients (8-35 years; 8 males, 6 females) were enrolled with baseline homocysteine levels 161 ± 67 μM. The study found high-dose taurine to be safe when excluding preexisting hypertriglyceridemia. Taurine pharmacokinetics showed a rapid peak level returning to near normal levels at 12 hours, but had slow accumulation and elevated predosing levels after 4 days of treatment. Only a single parameter of oxidative stress, 2,3-dinor-8-isoprostaglandin-F2α, was elevated at baseline, with no elevated inflammatory parameters, and no change in FMD values overall. Taurine had no effect on any of these parameters. However, the effect of taurine was strongly related to pretreatment FMD values; and taurine significantly improved FMD in the subset of individuals with pretreatment FMD values <10% and in individuals with homocysteine levels >125 μM, pertinent to endothelial function.
Conclusion
Taurine improves endothelial function in CBS-deficient homocystinuria in patients with preexisting reduced function.
CONFLICT OF INTEREST
All authors declare that they do not have a conflict of interest.
Supporting Information
| Filename | Description |
|---|---|
| jimd12085-sup-0001-AppendixS1.pdfPDF document, 1 MB |
Figure S1 Biochemistry of homocystinuria. Enzymes involved in the metabolism of homocysteine and cysteine, and the synthesis of taurine and of glutathione: cystathionine γ-lyase CTH; cystathionine β-synthase CBS; 5-methyltetrahydrofolate-homocysteine-S-methyltransferase MTR and its reductase MTRR; betaine-homocysteine methytransferase BHMT; S-adenosylhomocysteine hydrolase AHCY; methionine adenosyltransferase MAT1A; cysteine dioxygenase CDO; cysteine sulfinic acid decarboxylase CSAD; glutamate oxaloacetate aminotransferase GOT1; glutathione synthetase: GSS; OPLAH: 5-oxoprolinase: OPLAH; γ-glutamylcysteine: GGLC and GCLM genes; γ-glutamyltransferase GGT1; γ-glutamylcyclotransferase GGCT; adenosine kinase ADK Figure S2 Pharmacokinetic models show a good fit. Observed log concentrations are plotted against predicted concentrations of taurine from typical values of pharmacokinetic parameters (A) and from individual values of pharmacokinetic parameters (B). (C) Conditional weighted residuals vs population predicted log taurine concentrations; the red line is a Loess regression of the mean data and blue lines are the Loess at 5th and 95th percentiles. (D) Conditional weighted residuals vs time; the red line is a Loess regression of the mean data and the blue lines are the Loess at the 5th and the 95th percentiles Figure S3 Taurine treatment and flow-mediated dilation study in homocystinuria patients. Flow-mediated dilation studies in patients with homocystinuria before and after taurine treatment Appendix S1. Supporting Information. Table S1 Study method details Table S2: Genotype of enrolled patients with homocystinuria Table S3: Adverse events: Table S4: Safety laboratory summary Table S5: Triglyceride levels before and after taurine administration Table S6: Distribution of analytes Table S7: Pretreatment biomarkers of oxidative stress, inflammation, and homocysteine metabolites in CBSDH patients compared to controls: Mann-Whitney U test and correction for multiple comparison Table S8: Metabolites related to cystathionine β-synthase deficiency: comparison of patients untreated with betaine and those taking betaine Table S9: Literature on oxidative stress and inflammation in CBSDH patients |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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