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James M. Wilson - One of the best experts on this subject based on the ideXlab platform.
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determining the minimally effective dose of a clinical candidate aav vector in a mouse model of crigler najjar syndrome
Molecular therapy. Methods & clinical development, 2018Co-Authors: Jenny A Greig, Peter Bell, Deirdre Mcmenamin, Christine Draper, Edward A Chroscinski, Jayme M L Nordin, John T Gray, Laura K Richman, James M. WilsonAbstract:Liver Metabolism disorders are attractive targets for gene therapy, because low vector doses can reverse the buildup of toxic metabolites in the blood. Crigler-Najjar syndrome is an inherited disorder of Bilirubin Metabolism that is caused by the absence of uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) activity. This syndrome is characterized by hyperBilirubinemia and jaundice. Unfortunately, current phototherapy treatment is not effective long term. We intravenously injected phototherapy-rescued adult UGT1 knockout mice with 2.5 × 1010–2.5 × 1013 genome copies (GC)/kg of a clinical candidate vector, AAV8.TBG.hUGT1A1co, to study the treatment of disease compared to vehicle-only control mice. There were no apparent vector-related laboratory or clinical sequelae; the only abnormalities in clinical pathology were elevations in liver transaminases, primarily in male mice at the highest vector dose. Minimal to mild histopathological findings were present in control and vector-administered male mice. At vector doses greater than 2.5 × 1011 GC/kg, we observed a reversal of total Bilirubin levels to wild-type levels. Based on a significant reduction in serum total Bilirubin levels, we determined the minimally effective dose in this mouse model of Crigler-Najjar syndrome to be 2.5 × 1011 GC/kg.
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Determining the Minimally Effective Dose of a Clinical Candidate AAV Vector in a Mouse Model of Crigler-Najjar Syndrome
'Elsevier BV', 2018Co-Authors: Jenny A Greig, Peter Bell, Deirdre Mcmenamin, Christine Draper, Edward A Chroscinski, Jayme M L Nordin, John T Gray, Laura K Richman, James M. WilsonAbstract:Liver Metabolism disorders are attractive targets for gene therapy, because low vector doses can reverse the buildup of toxic metabolites in the blood. Crigler-Najjar syndrome is an inherited disorder of Bilirubin Metabolism that is caused by the absence of uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) activity. This syndrome is characterized by hyperBilirubinemia and jaundice. Unfortunately, current phototherapy treatment is not effective long term. We intravenously injected phototherapy-rescued adult UGT1 knockout mice with 2.5 × 1010–2.5 × 1013 genome copies (GC)/kg of a clinical candidate vector, AAV8.TBG.hUGT1A1co, to study the treatment of disease compared to vehicle-only control mice. There were no apparent vector-related laboratory or clinical sequelae; the only abnormalities in clinical pathology were elevations in liver transaminases, primarily in male mice at the highest vector dose. Minimal to mild histopathological findings were present in control and vector-administered male mice. At vector doses greater than 2.5 × 1011 GC/kg, we observed a reversal of total Bilirubin levels to wild-type levels. Based on a significant reduction in serum total Bilirubin levels, we determined the minimally effective dose in this mouse model of Crigler-Najjar syndrome to be 2.5 × 1011 GC/kg. Keywords: Crigler-Najjar Syndrome, adeno-associated virus, Bilirubin, live
Douglas J Clarke - One of the best experts on this subject based on the ideXlab platform.
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bile Bilirubin pigment analysis in disorders of Bilirubin Metabolism in early infancy
Archives of Disease in Childhood, 2001Co-Authors: P J Mckiernan, S V Beath, M A Preece, D Baty, Deirdre A Kelly, B Burchell, Douglas J ClarkeAbstract:BACKGROUND—Early and accurate diagnosis of Crigler-Najjar syndrome, which causes prolonged unconjugated hyperBilirubinaemia in infancy, is important, as orthotopic liver transplantation is the definitive treatment. AIM—To determine whether Bilirubin pigment analysis of bile in infants with prolonged unconjugated hyperBilirubinaemia provides useful diagnostic information in the first 3 months of life. METHODS—Retrospective review of patients with prolonged unconjugated hyperBilirubinaemia referred to the liver unit, Birmingham Children's Hospital, for the diagnosis of Crigler-Najjar syndrome. Bile Bilirubin pigment composition was determined by high performance liquid chromatography. Initial diagnoses were made based on the result of bile Bilirubin pigment composition. Final diagnoses were made after reviewing the clinical course, response to phenobarbitone, repeat bile Bilirubin pigment composition analysis, and genetic studies. RESULTS—Between 1992 and 1999, nine infants aged less than 3 months of age with prolonged hyperBilirubinaemia underwent bile Bilirubin pigment analyses. Based on these, two children were diagnosed with Crigler-Najjar syndrome (CNS) type 1, six with CNS type 2,and one with Gilbert's syndrome. Five children whose initial diagnosis was CNS type 2 had resolution of jaundice and normalisation of serum Bilirubin after discontinuing phenobarbitone, and these cases were thought to be normal or to have Gilbert's syndrome. One of the initial cases of CNS type 1 responded to phenobarbitone with an 80% reduction in serum Bilirubin consistent with CNS type 2. In all, the diagnoses of six cases needed to be reviewed. CONCLUSIONS—Early bile pigment analysis, performed during the first 3 months of life, often shows high levels of unconjugated Bilirubin or Bilirubin monoconjugates, leading to the incorrect diagnosis of both type 1 and type 2 Crigler-Najjar syndrome.
Li Jin - One of the best experts on this subject based on the ideXlab platform.
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quantitative trait analysis of polymorphisms in two Bilirubin Metabolism enzymes to physiologic Bilirubin levels in chinese newborns
The Journal of Pediatrics, 2014Co-Authors: Youyou Zhou, Sannan Wang, Weifeng Zha, Qianqian Peng, Ying Chen, Li JinAbstract:Objective To explore the effects of variants in Uridine Diphosphate Glucuronosyl Transferase 1A1 ( UGT1A1 ) and Heme Oxygenase-1 ( HMOX1 ) on daily physiological Bilirubin levels and Bilirubin changes during the first week after birth in Chinese newborns. Both UGT1A1 and HMOX1 code rate-limiting enzymes in the Bilirubin Metabolism pathway. Study design We conducted a retrospective quantitative trait study to analyze 4154 daily Bilirubin values, 3129 Bilirubin changes, and 11 polymorphisms of 988 newborns during the natural course of physiological hyperBilirubinemia. Results For UGT1A1, we found minor allele A of rs4148323 (G211A, UGT1A1 *6) contributed to higher daily Bilirubin levels on days 4-6 (with contributions to variations increasing from 4.8% to 12.3%), minor allele T of rs887829 (c-364t) contributed to lower daily Bilirubin levels for days 6 and 7 (with contributions to variations increasing from 7.0% to 10.2%) ( P n repeat ( UGT1A1 *28), and haplotype T-long-G at rs887829-(TA) n -rs4148323 were associated with a decrease in Bilirubin levels from day 5 to day 6 ( P HMOX1 was found. Conclusion Bilirubin levels and changes during the middle and late parts of the first week were attributed to variants and haplotypes in UGT1A1 . This quantitative trait study may provide a more robust statistical method for determining the association of genetic factors and Bilirubin kinetics to predict the development of neonatal Bilirubin in early postnatal life.
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association of polymorphisms in four Bilirubin Metabolism genes with serum Bilirubin in three asian populations
Human Mutation, 2009Co-Authors: Rong Lin, Xiaofeng Wang, Yi Wang, Feng Zhang, Ying Wang, Momiao Xiong, Wei Huang, Li JinAbstract:Numerous studies have shown that the (TA)n repeat polymorphism in the uridine diphosphate glycosyltransferase 1 (UGT1A1) gene promoter is associated with hyperBilirubinemia. Several studies also indicated that single nucleotide polymorphism (SNP) rs4148323:G>A at Exon 1 of UGT1A1 is associated with hyperBilirubinemia. However, it remains unclear what role the polymorphisms play in influencing serum total Bilirubin (TBIL) levels in general populations, and whether polymorphisms in other genes involved in the Bilirubin Metabolism pathway are associated with TBIL levels. The present study addressed these questions by investigating the association of four Bilirubin Metabolism genes with TBIL levels in three Asian populations: 11 genetic polymorphisms in heme oxygenase-1 (HMOX1); biliverdin reductase A (BLVRA); solute carrier organic anion transporter family member 1B1 (SLCO1B1); and UGT1A1. The populations consisted of 502 Kazak herdsmen, 769 Uyghur farmers, and 789 Han farmers, with distinct genetic backgrounds. UGT1A1 was found to be associated with the (TA)(7) allele of the (TA)n repeat polymorphism. We also showed that the A allele of SNP rs4148323:G>A was strongly associated with high TBIL levels in all three populations (each P A to phenotypic variations in all three populations. Finally, we observed that significant differences of TBIL levels existed among the three populations; however, this could not be completely explained by the differences at the (TA)n repeat polymorphism and SNP rs4148323:G>A.
Jenny A Greig - One of the best experts on this subject based on the ideXlab platform.
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determining the minimally effective dose of a clinical candidate aav vector in a mouse model of crigler najjar syndrome
Molecular therapy. Methods & clinical development, 2018Co-Authors: Jenny A Greig, Peter Bell, Deirdre Mcmenamin, Christine Draper, Edward A Chroscinski, Jayme M L Nordin, John T Gray, Laura K Richman, James M. WilsonAbstract:Liver Metabolism disorders are attractive targets for gene therapy, because low vector doses can reverse the buildup of toxic metabolites in the blood. Crigler-Najjar syndrome is an inherited disorder of Bilirubin Metabolism that is caused by the absence of uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) activity. This syndrome is characterized by hyperBilirubinemia and jaundice. Unfortunately, current phototherapy treatment is not effective long term. We intravenously injected phototherapy-rescued adult UGT1 knockout mice with 2.5 × 1010–2.5 × 1013 genome copies (GC)/kg of a clinical candidate vector, AAV8.TBG.hUGT1A1co, to study the treatment of disease compared to vehicle-only control mice. There were no apparent vector-related laboratory or clinical sequelae; the only abnormalities in clinical pathology were elevations in liver transaminases, primarily in male mice at the highest vector dose. Minimal to mild histopathological findings were present in control and vector-administered male mice. At vector doses greater than 2.5 × 1011 GC/kg, we observed a reversal of total Bilirubin levels to wild-type levels. Based on a significant reduction in serum total Bilirubin levels, we determined the minimally effective dose in this mouse model of Crigler-Najjar syndrome to be 2.5 × 1011 GC/kg.
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Determining the Minimally Effective Dose of a Clinical Candidate AAV Vector in a Mouse Model of Crigler-Najjar Syndrome
'Elsevier BV', 2018Co-Authors: Jenny A Greig, Peter Bell, Deirdre Mcmenamin, Christine Draper, Edward A Chroscinski, Jayme M L Nordin, John T Gray, Laura K Richman, James M. WilsonAbstract:Liver Metabolism disorders are attractive targets for gene therapy, because low vector doses can reverse the buildup of toxic metabolites in the blood. Crigler-Najjar syndrome is an inherited disorder of Bilirubin Metabolism that is caused by the absence of uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) activity. This syndrome is characterized by hyperBilirubinemia and jaundice. Unfortunately, current phototherapy treatment is not effective long term. We intravenously injected phototherapy-rescued adult UGT1 knockout mice with 2.5 × 1010–2.5 × 1013 genome copies (GC)/kg of a clinical candidate vector, AAV8.TBG.hUGT1A1co, to study the treatment of disease compared to vehicle-only control mice. There were no apparent vector-related laboratory or clinical sequelae; the only abnormalities in clinical pathology were elevations in liver transaminases, primarily in male mice at the highest vector dose. Minimal to mild histopathological findings were present in control and vector-administered male mice. At vector doses greater than 2.5 × 1011 GC/kg, we observed a reversal of total Bilirubin levels to wild-type levels. Based on a significant reduction in serum total Bilirubin levels, we determined the minimally effective dose in this mouse model of Crigler-Najjar syndrome to be 2.5 × 1011 GC/kg. Keywords: Crigler-Najjar Syndrome, adeno-associated virus, Bilirubin, live
P J Mckiernan - One of the best experts on this subject based on the ideXlab platform.
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bile Bilirubin pigment analysis in disorders of Bilirubin Metabolism in early infancy
Archives of Disease in Childhood, 2001Co-Authors: P J Mckiernan, S V Beath, M A Preece, D Baty, Deirdre A Kelly, B Burchell, Douglas J ClarkeAbstract:BACKGROUND—Early and accurate diagnosis of Crigler-Najjar syndrome, which causes prolonged unconjugated hyperBilirubinaemia in infancy, is important, as orthotopic liver transplantation is the definitive treatment. AIM—To determine whether Bilirubin pigment analysis of bile in infants with prolonged unconjugated hyperBilirubinaemia provides useful diagnostic information in the first 3 months of life. METHODS—Retrospective review of patients with prolonged unconjugated hyperBilirubinaemia referred to the liver unit, Birmingham Children's Hospital, for the diagnosis of Crigler-Najjar syndrome. Bile Bilirubin pigment composition was determined by high performance liquid chromatography. Initial diagnoses were made based on the result of bile Bilirubin pigment composition. Final diagnoses were made after reviewing the clinical course, response to phenobarbitone, repeat bile Bilirubin pigment composition analysis, and genetic studies. RESULTS—Between 1992 and 1999, nine infants aged less than 3 months of age with prolonged hyperBilirubinaemia underwent bile Bilirubin pigment analyses. Based on these, two children were diagnosed with Crigler-Najjar syndrome (CNS) type 1, six with CNS type 2,and one with Gilbert's syndrome. Five children whose initial diagnosis was CNS type 2 had resolution of jaundice and normalisation of serum Bilirubin after discontinuing phenobarbitone, and these cases were thought to be normal or to have Gilbert's syndrome. One of the initial cases of CNS type 1 responded to phenobarbitone with an 80% reduction in serum Bilirubin consistent with CNS type 2. In all, the diagnoses of six cases needed to be reviewed. CONCLUSIONS—Early bile pigment analysis, performed during the first 3 months of life, often shows high levels of unconjugated Bilirubin or Bilirubin monoconjugates, leading to the incorrect diagnosis of both type 1 and type 2 Crigler-Najjar syndrome.