1
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Abdelhamed W, El-Kassas M. Rare liver diseases in Egypt: Clinical and epidemiological characterization. Arab J Gastroenterol 2024; 25:75-83. [PMID: 38228442 DOI: 10.1016/j.ajg.2023.12.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 12/04/2023] [Accepted: 12/16/2023] [Indexed: 01/18/2024]
Abstract
Illnesses that afflict a tiny number of individuals are referred to as rare diseases (RDs), sometimes called orphan diseases. The local healthcare systems are constantly under financial, psychological, and medical strain due to low incidence rates, unusual presentations, flawed diagnostic standards, and a lack of treatment alternatives for these RDs. The effective management of the once widely spread viral hepatitis B and C has altered the spectrum of liver diseases in Egypt during the last several years. The detection of uncommon disorders such as autoimmune, cholestatic, and hereditary liver diseases has also been made easier by the increasing knowledge and greater accessibility of specific laboratory testing. Finally, despite Egypt's large population, there are more uncommon liver disorders than previously thought. This review article discusses the clinical and epidemiological characteristics of a few uncommon liver disorders and the information currently accessible concerning these illnesses in Egypt.
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Affiliation(s)
- Walaa Abdelhamed
- Endemic Medicine Department, Faculty of Medicine, Sohag University, Sohag, Egypt
| | - Mohamed El-Kassas
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, Egypt.
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2
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Quaglia A, Roberts EA, Torbenson M. Developmental and Inherited Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:122-294. [DOI: 10.1016/b978-0-7020-8228-3.00003-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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3
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Rijal D, Rijal P, Bohare SM, Chaudhari AS, Dhungel M, Agarwal M, Bhatta P, Dhakal TR, Bishwokarma A, Kafle P. A rare case of Crigler-Najjar syndrome type 2: A case report and literature review. Clin Case Rep 2023; 11:e8176. [PMID: 38028034 PMCID: PMC10643321 DOI: 10.1002/ccr3.8176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 10/19/2023] [Accepted: 10/28/2023] [Indexed: 12/01/2023] Open
Abstract
Key Clinical Message Crigler-Najjar syndrome type 2 should be suspected in any young patient presenting with isolated indirect hyperbilirubinemia where all other common etiologies have been excluded. It is a relatively benign condition that responds to phenobarbitone. Abstract Crigler-Najjar syndrome (CNS) type 2 is an inborn cause of isolated indirect hyperbilirubinemia characterized by a partial deficiency of the enzyme uridine 5'-diphosphate-glucuronosyltransferase (UGT) responsible for bilirubin conjugation. Typically, this condition is diagnosed based on clinical manifestations, supplemented by enzyme analysis if feasible, and exhibits a significant response to phenobarbitone, known for its enzyme-inducing properties. In this case, we present a young male patient who had experienced recurrent isolated indirect hyperbilirubinemia since early childhood, with negative results in the hemolytic workup. The patient exhibited a UGT1A1 gene defect and demonstrated a highly favorable response to phenobarbitone treatment. The purpose of this report is to raise awareness among physicians about this benign condition and underscore the importance of avoiding unnecessary investigations.
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Affiliation(s)
- Divas Rijal
- Department of Critical Care medicineTribhuvan University Teaching Hospital, Maharajgunj Medical CampusKathmanduNepal
| | - Prabhat Rijal
- Department of Internal MedicineAll India Institute of Medical SciencesRishikeshUttarakhandIndia
| | - Shyam Murti Bohare
- Department of Internal MedicineAll India Institute of Medical SciencesRishikeshUttarakhandIndia
| | - Ashish Sanjay Chaudhari
- Department of Internal MedicineAll India Institute of Medical SciencesRishikeshUttarakhandIndia
| | | | - Mayank Agarwal
- Department of Internal MedicineAll India Institute of Medical SciencesRishikeshUttarakhandIndia
| | - Pramish Bhatta
- Tribhuvan University Teaching Hospital, Maharajgunj Medical CampusKathmanduNepal
| | - Tulsi Ram Dhakal
- Tribhuvan University Teaching Hospital, Maharajgunj Medical CampusKathmanduNepal
| | - Anjali Bishwokarma
- Tribhuvan University Teaching Hospital, Maharajgunj Medical CampusKathmanduNepal
| | - Pooja Kafle
- Department of Critical Care medicineTribhuvan University Teaching Hospital, Maharajgunj Medical CampusKathmanduNepal
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4
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Kovačić Perica M, Todorić I, Marčinković N, Džepina P, Aničić MN, Mrzljak A, Vuković J. Case report: Crigler-Najjar syndrome type 1 in Croatia-more than a one in a million: a case series. Front Pediatr 2023; 11:1276349. [PMID: 37928349 PMCID: PMC10620791 DOI: 10.3389/fped.2023.1276349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Accepted: 10/02/2023] [Indexed: 11/07/2023] Open
Abstract
Crigler-Najjar syndrome (CNS) is an exceedingly rare autosomal recessive disease with an estimated incidence of 1 in a million live births. CNS type 1 (CNS1) is the most severe form, characterized by severe unconjugated hyperbilirubinemia since birth due to the absence of hepatic uridine 5'-diphosphate glucuronyltransferase (UGT1A1) activity. Daily phototherapy (PT) and liver transplant (LT) are the mainstays of therapy. Here, we present a higher-than-expected incidence of CNS1 in Croatia (6,1 in a million). In the last 31 years, we treated eight CNS1 patients from five families with no reported consanguinity. Four patients are descendants of an isolated enclave in Kosovo with a small gene pool and a high potential for inbreeding. Severe unconjugated hyperbilirubinemia was verified in a neonatal period and PT was initiated. Four patients underwent LT from living-related donors. One of them had unsuccessful hepatocyte transplantation earlier. LT was successful in three patients, and one patient died due to primary graft dysfunction. Four patients are currently treated with 9-12 h daily PT with inconsistent disease control, and gradually increasing bilirubin. One patient developed kernicterus before LT, while others have normal psychomotor development and no neurologic impairment. Genetic testing of the UGT1A1 gene in six patients from three families revealed three different homozygous mutations (c.722_723 delAG, c.717_718 delAG, and c.1021 C >T), all previously described in other populations. There is a possibility of the founder effect as an explanation for the higher incidence of CNS1 in at least a subgroup of Croatians.
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Affiliation(s)
| | - Ivana Todorić
- Department of Pediatrics, University Hospital Center Zagreb, Zagreb, Croatia
| | - Nedo Marčinković
- Department of Pediatrics, University Hospital Center Zagreb, Zagreb, Croatia
| | - Petra Džepina
- Department of Pediatrics, University Hospital Center Zagreb, Zagreb, Croatia
| | - Mirna Natalija Aničić
- Department of Pediatrics, University Hospital Center Zagreb, Zagreb, Croatia
- School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Anna Mrzljak
- School of Medicine, University of Zagreb, Zagreb, Croatia
- Department of Gastroenterology and Hepatology, University Hospital Center Zagreb, Zagreb, Croatia
| | - Jurica Vuković
- Department of Pediatrics, University Hospital Center Zagreb, Zagreb, Croatia
- School of Medicine, University of Zagreb, Zagreb, Croatia
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5
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Greig JA, Chorazeczewski JK, Chowdhary V, Smith MK, Jennis M, Tarrant JC, Buza EL, Coughlan K, Martini PG, Wilson JM. Lipid nanoparticle-encapsulated mRNA therapy corrects serum total bilirubin level in Crigler-Najjar syndrome mouse model. Mol Ther Methods Clin Dev 2023; 29:32-39. [PMID: 36936447 PMCID: PMC10017950 DOI: 10.1016/j.omtm.2023.02.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Accepted: 02/10/2023] [Indexed: 02/17/2023]
Abstract
Crigler-Najjar syndrome is a rare disorder of bilirubin metabolism caused by uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) mutations characterized by hyperbilirubinemia and jaundice. No cure currently exists; treatment options are limited to phototherapy, whose effectiveness diminishes over time, and liver transplantation. Here, we evaluated the therapeutic potential of systemically administered, lipid nanoparticle-encapsulated human UGT1A1 (hUGT1A1) mRNA therapy in a Crigler-Najjar mouse model. Ugt1 knockout mice were rescued from lethal post-natal hyperbilirubinemia by phototherapy. These adult Ugt1 knockout mice were then administered a single lipid nanoparticle-encapsulated hUGT1A1 mRNA dose. Within 24 h, serum total bilirubin levels decreased from 15 mg/dL (256 μmol/L) to <0.5 mg/dL (9 μmol/L), i.e., slightly above wild-type levels. This reduction was sustained for 2 weeks before bilirubin levels rose and returned to pre-treatment levels by day 42 post-administration. Sustained reductions in total bilirubin levels were achieved by repeated administration of the mRNA product in a frequency-dependent manner. We were also able to rescue the neonatal lethality phenotype seen in Ugt1 knockout mice with a single lipid nanoparticle dose, which suggests that this may be a treatment modality appropriate for metabolic crisis situations. Therefore, lipid nanoparticle-encapsulated hUGT1A1 mRNA may represent a potential treatment for Crigler-Najjar syndrome.
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Affiliation(s)
- Jenny A. Greig
- Gene Therapy Program, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | | | - Vivek Chowdhary
- Gene Therapy Program, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Melanie K. Smith
- Gene Therapy Program, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Matthew Jennis
- Gene Therapy Program, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - James C. Tarrant
- Gene Therapy Program, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Elizabeth L. Buza
- Gene Therapy Program, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | | | | | - James M. Wilson
- Gene Therapy Program, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Corresponding author. James M. Wilson, MD, PhD, Gene Therapy Program, Perelman School of Medicine, University of Pennsylvania, 125 South 31st Street, Suite 1200, Philadelphia, PA 19104, USA.
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6
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Aronson SJ, Junge N, Trabelsi M, Kelmemi W, Hubert A, Brigatti KW, Fox MD, de Knegt RJ, Escher JC, Ginocchio VM, Iorio R, Zhu Y, Özçay F, Rahim F, El-Shabrawi MHF, Shteyer E, Di Giorgio A, D'Antiga L, Mingozzi F, Brunetti-Pierri N, Strauss KA, Labrune P, Mrad R, Baumann U, Beuers U, Bosma PJ. Disease burden and management of Crigler-Najjar syndrome: Report of a world registry. Liver Int 2022; 42:1593-1604. [PMID: 35274801 DOI: 10.1111/liv.15239] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 03/03/2022] [Accepted: 03/07/2022] [Indexed: 12/24/2022]
Affiliation(s)
- Sem J Aronson
- Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology & Metabolism, Amsterdam University Medical Centers, Amsterdam, the Netherlands
| | - Norman Junge
- Division for Pediatric Gastroenterology and Hepatology, Department of Pediatric Kidney, Liver, and Metabolic Diseases, Hannover Medical School, Hannover, Germany
| | - Mediha Trabelsi
- Laboratoire de Génétique Humaine, Faculté de Médecine de Tunis (Laboratory of Human Genetics, Faculty of Medicine of Tunis, Université de Tunis El Manar (University of Tunis El Manar), Tunis, Tunisia
- Service des Maladies Congénitales et Héréditaires (Department of Hereditary and Congenital Disorders), Hôpital Charles Nicolle (Charles Nicolle Hospital), Tunis, Tunisia
| | - Wided Kelmemi
- Laboratoire de Génétique Humaine, Faculté de Médecine de Tunis (Laboratory of Human Genetics, Faculty of Medicine of Tunis, Université de Tunis El Manar (University of Tunis El Manar), Tunis, Tunisia
| | - Aurelie Hubert
- Department of Hereditary Diseases of Hepatic Metabolism, Hôpital Antoine Béclère, Clamart, France
| | | | - Michael D Fox
- Clinic for Special Children, Strasburg, Pennsylvania, USA
- Department of Pediatrics, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Robert J de Knegt
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Sophia Children's Hospital, Rotterdam, the Netherlands
| | - Johanna C Escher
- Department of Pediatric Gastroenterology, Erasmus University Medical Center, Sophia Children's Hospital, Rotterdam, the Netherlands
| | - Virginia M Ginocchio
- Department of Translational Medicine, Federico II University of Naples, Naples, Italy
| | - Raffaele Iorio
- Department of Translational Medicine, Federico II University of Naples, Naples, Italy
| | - Yan Zhu
- Third Military Medical University, Chongqing, China
| | - Figen Özçay
- Department of Pediatric Gastroenterology, Baskent University Faculty of Medicine, Ankara, Turkey
| | - Fakher Rahim
- Metabolomics and Genomics Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- Health research Institute, Research Center of Thalassemia & Hemoglobinopathy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mortada H F El-Shabrawi
- Department of Pediatrics and Pediatric Hepatology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Eyal Shteyer
- Paediatric Gastroenterology and Nutrition, Shaare Zedek Medical Center, Jerusalem, Israel
| | - Angelo Di Giorgio
- Department of Paediatric Gastroenterology, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy
| | - Lorenzo D'Antiga
- Department of Paediatric Gastroenterology, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy
| | | | - Nicola Brunetti-Pierri
- Department of Translational Medicine, Federico II University of Naples, Naples, Italy
- Telethon Institute of Genetics and Medicine, Pozzuoli, Italy
| | - Kevin A Strauss
- Clinic for Special Children, Strasburg, Pennsylvania, USA
- Departments of Pediatrics and Molecular, Cell & Cancer Biology, University of Massachusetts School of Medicine, Worcester, Massachusetts, USA
| | - Philippe Labrune
- Department of Hereditary Diseases of Hepatic Metabolism, Hôpital Antoine Béclère, Clamart, France
| | - Ridha Mrad
- Laboratoire de Génétique Humaine, Faculté de Médecine de Tunis (Laboratory of Human Genetics, Faculty of Medicine of Tunis, Université de Tunis El Manar (University of Tunis El Manar), Tunis, Tunisia
- Service des Maladies Congénitales et Héréditaires (Department of Hereditary and Congenital Disorders), Hôpital Charles Nicolle (Charles Nicolle Hospital), Tunis, Tunisia
| | - Ulrich Baumann
- Division for Pediatric Gastroenterology and Hepatology, Department of Pediatric Kidney, Liver, and Metabolic Diseases, Hannover Medical School, Hannover, Germany
| | - Ulrich Beuers
- Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology & Metabolism, Amsterdam University Medical Centers, Amsterdam, the Netherlands
| | - Piter J Bosma
- Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology & Metabolism, Amsterdam University Medical Centers, Amsterdam, the Netherlands
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7
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Mondal S, Pan N, Ghosh R, Bera A, Mukherjee D, Maji TK, Adhikari A, Ghosh S, Bhattacharya C, Pal SK. Interaction of a Jaundice Marker Molecule with Redox Modulatory Nano Hybrid: A Combined Electrochemical and Spectroscopic Study towards the Development of a Theranostics Tool. ChemMedChem 2022; 17:e202100660. [DOI: 10.1002/cmdc.202100660] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Indexed: 11/10/2022]
Affiliation(s)
- Susmita Mondal
- S N Bose National Centre for Basic Sciences CBMS Block JD, Sector III, Salt Lake 700106 Kolkata INDIA
| | - Nivedita Pan
- S N Bose National Centre for Basic Sciences Department of Chemical, Biological, Macromolecular Sciences Block JD, Sector III, Salt Lake 700106 kolkata INDIA
| | - Ria Ghosh
- S N Bose National Centre for Basic Sciences Department of Chemical, Biological and Macromolecular Sciences Block JD, Sector III, Salt Lake 700106 Kolkata INDIA
| | - Arpan Bera
- S N Bose National Centre for Basic Sciences Department of Chemical, Biological and Macromolecular Sciences Block JD, Sector III, Salt Lake 700106 Kolkata INDIA
| | - Dipanjan Mukherjee
- S N Bose National Centre for Basic Sciences Department of Chemical, Biological and Macromolecular Sciences Block JD, Sector III, Salt Lake 700106 Kolkata INDIA
| | - Tuhin Kumar Maji
- S N Bose National Centre for Basic Sciences Department of Chemical, Biological and Macromolecular Sciences Block JD, Sector III, Salt Lake 700106 Kolkata INDIA
| | - Anirudddha Adhikari
- S N Bose National Centre for Basic Sciences Department of Chemical, Biological and Macromolecular Sciences Block JD, Sector III, Salt Lake 700106 Kolkata INDIA
| | - Sangeeta Ghosh
- IIEST Shibpur: Indian Institute of Engineering Science and Technology Department of Chemistry Howrah-711103, West Bengal, INDIA 711103 Howrah INDIA
| | - Chinmoy Bhattacharya
- IISET Department of Chemistry Howrah-711103, West Bengal, INDIA 711103 Howrah INDIA
| | - Samir Kumar Pal
- SNBNCBS CBMS Block JD, Sector IIISalt Lake City 700098 Kolkata INDIA
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8
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Vimalesvaran S, Dhawan A. Liver transplantation for pediatric inherited metabolic liver diseases. World J Hepatol 2021; 13:1351-1366. [PMID: 34786171 PMCID: PMC8568579 DOI: 10.4254/wjh.v13.i10.1351] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 06/23/2021] [Accepted: 08/20/2021] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation (LT) remains the gold standard treatment for end stage liver disease in the pediatric population. For liver based metabolic disorders (LBMDs), the decision for LT is predicated on a different set of paradigms. With improved outcomes post-transplantation, LT is no longer merely life saving, but has the potential to also significantly improve quality of life. This review summarizes the clinical presentation, medical treatment and indications for LT for some of the common LBMDs. We also provide a practical update on the dilemmas and controversies surrounding the indications for transplantation, surgical considerations and prognosis and long terms outcomes for pediatric LT in LBMDs. Important progress has been made in understanding these diseases in recent years and with that we outline some of the new therapies that have emerged.
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Affiliation(s)
- Sunitha Vimalesvaran
- Paediatric Liver GI and Nutrition Center, King's College Hospital, London SE5 9RS, United Kingdom
| | - Anil Dhawan
- Paediatric Liver GI and Nutrition Center, King's College Hospital, London SE5 9RS, United Kingdom
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9
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Tcaciuc E, Podurean M, Tcaciuc A. Management of Crigler-Najjar syndrome. Med Pharm Rep 2021; 94:S64-S67. [PMID: 34527915 DOI: 10.15386/mpr-2234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Crigler-Najjar syndrome is a rare autosomal recessive inherited non-hemolytic unconjugated hyperbilirubinemia caused by UDP-glucuronosyltransferase deficiency. There are two forms of this disorder. Type 1 disease is associated with severe jaundice and neurologic impairment due to bilirubin encephalopathy that can result in permanent neurologic sequelae. Type 2 disease is associated with a lower serum bilirubin concentration and affected patients survive into adulthood without neurologic impairment. Currently, liver transplantation is the only available therapeutic method for these patients. Developing new curative approaches is a clinical need.
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Affiliation(s)
- Eugen Tcaciuc
- Department of Internal Medicine, Nicolae Testemitanu State University of Medicine and Pharmacy, Chisinau, Republic of Moldova
| | - Mariana Podurean
- Department of Internal Medicine, Nicolae Testemitanu State University of Medicine and Pharmacy, Chisinau, Republic of Moldova
| | - Angela Tcaciuc
- Department of Internal Medicine, Nicolae Testemitanu State University of Medicine and Pharmacy, Chisinau, Republic of Moldova
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10
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Shi X, Bortolussi G, Bloemendaal LT, Duijst S, Muro AF, Bosma PJ. Low efficacy of recombinant SV40 in Ugt1a1-/- mice with severe inherited hyperbilirubinemia. PLoS One 2021; 16:e0250605. [PMID: 33891666 PMCID: PMC8064607 DOI: 10.1371/journal.pone.0250605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 04/10/2021] [Indexed: 11/25/2022] Open
Abstract
In contrast to AAV, Simian Virus 40 (rSV40) not inducing neutralizing antibodies (NAbs) allowing re-treatment seems a promising vector for neonatal treatment of inherited liver disorders. Several studies have reported efficacy of rSV40 in animal models for inherited liver diseases. In all studies the ubiquitous endogenous early promoter controlled transgene expression establishing expression in all transduced tissues. Restricting this expression to the target tissues reduces the risk of immune response to the therapeutic gene. In this study a liver specific rSV40 vector was generated by inserting a hepatocyte specific promoter. This increased the specificity of the expression of hUGT1A1 in vitro. However, in vivo the efficacy of rSV40 appeared too low to demonstrate tissue specificity while increasing the vector dose was not possible because of toxicity. In contrast to earlier studies, neutralizing antibodies were induced. Overall, the lack of a platform to produce high titered and pure rSV40 particles and the induction of NAbs, renders it a poor candidate for in vivo gene therapy.
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Affiliation(s)
- Xiaoxia Shi
- Amsterdam UMC, Tytgat Institute for Liver and Intestinal Research, AGEM, University of Amsterdam, Amsterdam, The Netherlands
- * E-mail:
| | - Giulia Bortolussi
- International Centre for Genetic Engineering and Biotechnology, Trieste, Italy
| | - Lysbeth ten Bloemendaal
- Amsterdam UMC, Tytgat Institute for Liver and Intestinal Research, AGEM, University of Amsterdam, Amsterdam, The Netherlands
| | - Suzanne Duijst
- Amsterdam UMC, Tytgat Institute for Liver and Intestinal Research, AGEM, University of Amsterdam, Amsterdam, The Netherlands
| | - Andrés F. Muro
- International Centre for Genetic Engineering and Biotechnology, Trieste, Italy
| | - Piter J. Bosma
- Amsterdam UMC, Tytgat Institute for Liver and Intestinal Research, AGEM, University of Amsterdam, Amsterdam, The Netherlands
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11
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Shi X, Aronson SJ, Ten Bloemendaal L, Duijst S, Bakker RS, de Waart DR, Bortolussi G, Collaud F, Oude Elferink RP, Muro AF, Mingozzi F, Ronzitti G, Bosma PJ. Efficacy of AAV8-h UGT1A1 with Rapamycin in neonatal, suckling, and juvenile rats to model treatment in pediatric CNs patients. MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT 2021; 20:287-297. [PMID: 33511243 PMCID: PMC7809245 DOI: 10.1016/j.omtm.2020.11.016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 11/28/2020] [Indexed: 12/18/2022]
Abstract
A clinical trial using adeno-associated virus serotype 8 (AAV8)-human uridine diphosphate glucuronosyltransferase 1A1 (hUGT1A1) to treat inherited severe unconjugated hyperbilirubinemia (Crigler-Najjar syndrome) is ongoing, but preclinical data suggest that long-term efficacy in children is impaired due to loss of transgene expression upon hepatocyte proliferation in a growing liver. This study aims to determine at what age long-term efficacy can be obtained in the relevant animal model and whether immune modulation allows re-treatment using the same AAV vector. Neonatal, suckling, and juvenile Ugt1a1-deficient rats received a clinically relevant dose of AAV8-hUGT1A1, and serum bilirubin levels and anti-AAV8 neutralizing antibodies (NAbs) in serum were monitored. The possibility of preventing the immune response toward the vector was investigated using a rapamycin-based regimen with daily intraperitoneal (i.p.) injections starting 2 days before and ending 21 days after vector administration. In rats treated at postnatal day 1 (P1) or P14, the correction was (partially) lost after 12 weeks, whereas the correction was stable in rats injected at P28. Combining initial vector administration with the immune-suppressive regimen prevented induction of NAbs in female rats, allowing at least partially effective re-administration. Induction of NAbs upon re-injection could not be prevented, suggesting that this strategy will be ineffective in patients with low levels of preexisting anti-AAV NAbs.
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Affiliation(s)
- Xiaoxia Shi
- Amsterdam UMC, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, AGEM, Meibergdreef 69-71, 1105 BK Amsterdam, the Netherlands
| | - Sem J Aronson
- Amsterdam UMC, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, AGEM, Meibergdreef 69-71, 1105 BK Amsterdam, the Netherlands
| | - Lysbeth Ten Bloemendaal
- Amsterdam UMC, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, AGEM, Meibergdreef 69-71, 1105 BK Amsterdam, the Netherlands
| | - Suzanne Duijst
- Amsterdam UMC, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, AGEM, Meibergdreef 69-71, 1105 BK Amsterdam, the Netherlands
| | - Robert S Bakker
- Amsterdam UMC, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, AGEM, Meibergdreef 69-71, 1105 BK Amsterdam, the Netherlands
| | - Dirk R de Waart
- Amsterdam UMC, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, AGEM, Meibergdreef 69-71, 1105 BK Amsterdam, the Netherlands
| | - Giulia Bortolussi
- International Centre for Genetic Engineering and Biotechnology, 34149 Trieste, Italy
| | - Fanny Collaud
- Genethon, 91000 Evry, France.,Université Paris-Saclay, Université d'Evry, INSERM, Genethon, Integrare Research Unit UMR S951, 91000 Evry, France
| | - Ronald P Oude Elferink
- Amsterdam UMC, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, AGEM, Meibergdreef 69-71, 1105 BK Amsterdam, the Netherlands
| | - Andrés F Muro
- International Centre for Genetic Engineering and Biotechnology, 34149 Trieste, Italy
| | | | - Giuseppe Ronzitti
- Genethon, 91000 Evry, France.,Université Paris-Saclay, Université d'Evry, INSERM, Genethon, Integrare Research Unit UMR S951, 91000 Evry, France
| | - Piter J Bosma
- Amsterdam UMC, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, AGEM, Meibergdreef 69-71, 1105 BK Amsterdam, the Netherlands
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12
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Ataollahi M, Dehghani SM, Anbardar MH, Shakorani P, Shahramian I, Salarzaei M, Parooie F. [Liver histologic changes in children with type 1 of Crigler-Najjar syndrome]. Arkh Patol 2021; 83:27-30. [PMID: 34609801 DOI: 10.17116/patol20218305127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
UNLABELLED Background. Crigler-Najjar syndrome (CNS) is a rare genetic disorder found in less than 1 per 1.000.000 births. It happens as a result of an error in UGT1A1 enzyme which can cause high unconjugated bilirubin levels. OBJECTIVE To describe liver histology changes in patients who have undergone liver transplantation. METHODS This retrospective cross-sectional study was performed to evaluate the liver pathologies of patients with type 1 of Crigler-Najjar syndrome (CNS1). We analyzed medical records and liver histologic specimens of 53 children who were transplanted in Namazi Hospital Organ Transplant Center affiliated with Shiraz University of Medical Sciences between 2009 and 2019. We studied the tissue of the explanted liver, which was replaced by transplants. Most of the patients were less than 2 years old, with an average age of 1.7 years. The collected data were analyzed using SPSS 22 software. RESULTS The prevalent pathology found in the liver of these patients was periportal fibrosis (96.2%). Cholestasis was the second common finding (94.3%) followed by pericentral fibrosis (86.7%) and ductal reaction (22.6%). A significant correlation was only present between phototherapy time and ductal reaction grade. CONCLUSION Our results indicated a high prevalence of fibrosis of different grades among CNS 1 patients which bolds the necessity of histologic examination before considering treatments such as gene therapy or hepatocyte transplantation.
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Affiliation(s)
- M Ataollahi
- Pediatric Gastroenterology and Hepatology of the Shiraz University of Medical Sciences, Shiraz, Iran
| | - S M Dehghani
- Pediatric Gastroenterology and Hepatology of the Shiraz University of Medical Sciences, Shiraz, Iran
| | - M H Anbardar
- Department of Pathology of the Shiraz University of Medical Sciences, Shiraz, Iran
| | - P Shakorani
- Department of pediatrics of the Shiraz University of Medical Sciences, Shiraz, Iran
| | - I Shahramian
- Pediatric Gastroenterology and Hepatology Research Center of the Zabol university of Medical Sciences, Zabol, Iran
| | - M Salarzaei
- Pediatric Gastroenterology and Hepatology Research Center of the Zabol university of Medical Sciences, Zabol, Iran
| | - F Parooie
- Pediatric Gastroenterology and Hepatology Research Center of the Zabol university of Medical Sciences, Zabol, Iran
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13
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Sanjel B, Shim WS. Recent advances in understanding the molecular mechanisms of cholestatic pruritus: A review. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165958. [PMID: 32896605 DOI: 10.1016/j.bbadis.2020.165958] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 08/21/2020] [Accepted: 09/01/2020] [Indexed: 02/06/2023]
Abstract
Cholestasis, a condition characterized by an abnormal decrease in bile flow, is accompanied by various symptoms such as pruritus. Although cholestatic pruritus is a prominent condition, its precise mechanisms have largely been elusive. Recently, advancements have been made for understanding the etiology and pathogenesis of cholestatic pruritus. The current review therefore focuses on summarizing the overall progress made in the elucidation of its molecular mechanisms. We have reviewed the available animal models on cholestasis to compare the differences between them, characterized potential pruritogens involved in cholestatic pruritus, and have summarized the receptor and ion channels implicated in the condition. Finally, we have discussed the available treatment options for alleviation of cholestatic pruritus. As our understanding of the mechanisms of cholestatic pruritus deepens, novel strategies to cure this condition are awaited.
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Affiliation(s)
- Babina Sanjel
- College of Pharmacy, Gachon University, Hambakmoero 191, Yeonsu-gu, Incheon 21936, Republic of Korea; Gachon Institute of Pharmaceutical Sciences, Hambakmoero 191, Yeonsu-gu, Incheon 21936, Republic of Korea
| | - Won-Sik Shim
- College of Pharmacy, Gachon University, Hambakmoero 191, Yeonsu-gu, Incheon 21936, Republic of Korea; Gachon Institute of Pharmaceutical Sciences, Hambakmoero 191, Yeonsu-gu, Incheon 21936, Republic of Korea.
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14
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A Quantitative In Vitro Potency Assay for Adeno-Associated Virus Vectors Encoding for the UGT1A1 Transgene. MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT 2020; 18:250-258. [PMID: 32637454 PMCID: PMC7327880 DOI: 10.1016/j.omtm.2020.06.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Accepted: 05/29/2020] [Indexed: 12/20/2022]
Abstract
Potency assessment of clinical-grade vector lots is crucial to support adeno-associated virus (AAV) vector release and is required for future marketing authorization. We have developed and validated a cell-based, quantitative potency assay that detects both transgenic expression and activity of an AAV8-hUGT1A1 vector, which is currently under clinical evaluation for the treatment of Crigler-Najjar syndrome. Potency of AAV8-hUGT1A1 was evaluated in vitro. After transduction of human hepatoma 7 (Huh7) cells, transgene-positive cells were quantified using flow cytometry and transgenic activity by a bilirubin conjugation assay. The in vitro potency of various AAV8-hUGT1A1 batches was compared with their potency in vivo. After AAV8-hUGT1A1 transduction, quantification of UGT1A1-expressing cells shows a linear dose-response relation (R2 = 0.98) with adequate intra-assay and inter-day reproducibility (coefficient of variation [CV] = 11.0% and 22.6%, respectively). In accordance, bilirubin conjugation shows a linear dose-response relation (R2 = 0.99) with adequate intra- and inter-day reproducibility in the low dose range (CV = 15.7% and 19.7%, respectively). Both in vitro potency assays reliably translate to in vivo efficacy of AAV8-hUGT1A1 vector lots. The described cell-based potency assay for AAV8-hUGT1A1 adequately determines transgenic UGT1A1 expression and activity, which is consistent with in vivo efficacy. This novel approach is suited for the determination of vector lot potency to support clinical-grade vector release.
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15
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Strauss KA, Ahlfors CE, Soltys K, Mazareigos GV, Young M, Bowser LE, Fox MD, Squires JE, McKiernan P, Brigatti KW, Puffenberger EG, Carson VJ, Vreman HJ. Crigler-Najjar Syndrome Type 1: Pathophysiology, Natural History, and Therapeutic Frontier. Hepatology 2020; 71:1923-1939. [PMID: 31553814 PMCID: PMC7909716 DOI: 10.1002/hep.30959] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Accepted: 09/04/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS We describe the pathophysiology, treatment, and outcome of Crigler-Najjar type 1 syndrome (CN1) in 28 UGT1A1 c.222C>A homozygotes followed for 520 aggregate patient-years. APPROACH AND RESULTS Unbound ("free") bilirubin (Bf ) was measured in patient sera to characterize the binding of unconjugated bilirubin (BT ) to albumin (A) and validate their molar concentration ratio (BT /A) as an index of neurological risk. Two custom phototherapy systems were constructed from affordable materials to provide high irradiance in the outpatient setting; light dose was titrated to keep BT /A at least 30% below intravascular BT binding capacity (i.e., BT /A = 1.0). Categorical clinical outcomes were ascertained by chart review, and a measure (Lf ) was used to quantify liver fibrosis. Unbound bilirubin had a nonlinear relationship to BT (R2 = 0.71) and BT /A (R2 = 0.76), and Bf as a percentage of BT correlated inversely to the bilirubin-albumin equilibrium association binding constant (R2 = 0.69), which varied 10-fold among individuals. In newborns with CN1, unconjugated bilirubin increased 4.3 ± 1.1 mg/dL per day. Four (14%) neonates developed kernicterus between days 14 and 45 postnatal days of life; peak BT ≥ 30 mg/dL and BT /A ≥ 1.0 mol:mol were equally predictive of perinatal brain injury (sensitivity 100%, specificity 93.3%, positive predictive value 88.0%), and starting phototherapy after age 13 days increased this risk 3.5-fold. Consistent phototherapy with 33-103 µW/cm2 •nm for 9.2 ± 1.1 hours/day kept BT and BT /A within safe limits throughout childhood, but BT increased 0.46 mg/dL per year to reach dangerous concentrations by 18 years of age. Liver transplantation (n = 17) normalized BT and eliminated phototherapy dependence. Liver explants showed fibrosis ranging from mild to severe. CONCLUSION Seven decades after its discovery, CN1 remains a morbid and potentially fatal disorder.
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Affiliation(s)
- Kevin A. Strauss
- Clinic for Special Children, Strasburg, PA,Penn-Lancaster General Hospital, Lancaster, PA,Departments of Pediatrics and Molecular, Cell & Cancer Biology, University of Massachusetts School of Medicine, Worcester, MA
| | - Charles E. Ahlfors
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
| | - Kyle Soltys
- Department of Surgery, Division of Pediatric Transplantation, Hillman Center for Pediatric Transplantation, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA
| | - George V. Mazareigos
- Department of Surgery, Division of Pediatric Transplantation, Hillman Center for Pediatric Transplantation, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA
| | | | | | - Michael D. Fox
- Clinic for Special Children, Strasburg, PA,Department of Pediatrics, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA,Diagnostic Referral Division, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE
| | - James E. Squires
- Division of Gastroenterology and Hepatology, Department of Pediatrics, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA
| | - Patrick McKiernan
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, UPMC Children’s Hospital of Pittsburgh and Pittsburgh Liver Research Center, Pittsburgh, PA
| | | | | | | | - Hendrik J. Vreman
- Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
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16
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Shroff H, Maddur H. Isolated Elevated Bilirubin. Clin Liver Dis (Hoboken) 2020; 15:153-156. [PMID: 32395242 PMCID: PMC7206321 DOI: 10.1002/cld.944] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Accepted: 01/26/2020] [Indexed: 02/04/2023] Open
Abstract
http://aasldpubs.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)2046-2484/video/15-4-reading-shroff-maddur a video presentation of this article http://aasldpubs.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)2046-2484/video/15-4-interview-shroff-maddur an interview with the author https://www.wileyhealthlearning.com/Activity/7088613/disclaimerspopup.aspx questions and earn CME.
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Affiliation(s)
- Hersh Shroff
- Division of Gastroenterology and HepatologyDepartment of MedicineNorthwestern UniversityChicagoIL
| | - Haripriya Maddur
- Division of Gastroenterology and HepatologyDepartment of MedicineNorthwestern UniversityChicagoIL
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17
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Dhawan A, Lawlor MW, Mazariegos GV, McKiernan P, Squires JE, Strauss KA, Gupta D, James E, Prasad S. Disease burden of Crigler-Najjar syndrome: Systematic review and future perspectives. J Gastroenterol Hepatol 2020; 35:530-543. [PMID: 31495946 DOI: 10.1111/jgh.14853] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Revised: 08/28/2019] [Accepted: 08/28/2019] [Indexed: 01/08/2023]
Abstract
BACKGROUND AND AIM Crigler-Najjar syndrome (CNS) results from biallelic mutations of UGT1A1 causing partial or total loss of uridine 5'-diphosphate glucuronyltransferase activity leading to unconjugated hyperbilirubinemia and its attendant risk for irreversible neurological injury (kernicterus). CNS is exceedingly rare and has been only partially characterized through relatively small studies, each comprising between two and 57 patients. METHODS A systematic literature review was conducted to consolidate data on the patient, caregiver, and societal burden of CNS. RESULTS Twenty-eight articles on clinical aspects of CNS were identified, but no published data on its humanistic or economic burden were found. In patients with complete UGT1A1 deficiency (type 1 CNS [CNS-I]), unconjugated bilirubin levels increase 3-6 mg/dL/day during the newborn period and reach neurologically dangerous levels between 5 and 14 days of age. Phototherapy is the mainstay of treatment but poses significant challenges to patients and their families. Despite consistent phototherapy, patients with CNS-I have worsening hyperbilirubinemia with advancing age. Liver transplantation is the only definitive therapy for CNS-I and is increasingly associated with excellent long-term survival but also incurs high costs, medical and surgical morbidities, and risks of immunosuppression. CONCLUSIONS Crigler-Najjar syndrome is associated with a substantial burden, even with existing standards of care. The development of novel disease-modifying therapies has the potential to reduce disease burden and improve the lives of CNS patients and their families.
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Affiliation(s)
- Anil Dhawan
- King's College Hospital NHS Foundation Trust, London, UK
| | - Michael W Lawlor
- Division of Pediatric Pathology, Department of Pathology and Laboratory Medicine and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI, USA
| | - George V Mazariegos
- Hillman Center for Pediatric Transplantation, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Patrick McKiernan
- Hillman Center for Pediatric Transplantation, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - James E Squires
- Hillman Center for Pediatric Transplantation, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | | | | | - Emma James
- Audentes Therapeutics, San Francisco, CA, USA
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18
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Aronson SJ, Veron P, Collaud F, Hubert A, Delahais V, Honnet G, de Knegt RJ, Junge N, Baumann U, Di Giorgio A, D'Antiga L, Ginocchio VM, Brunetti-Pierri N, Labrune P, Beuers U, Bosma PJ, Mingozzi F. Prevalence and Relevance of Pre-Existing Anti-Adeno-Associated Virus Immunity in the Context of Gene Therapy for Crigler-Najjar Syndrome. Hum Gene Ther 2020; 30:1297-1305. [PMID: 31502485 PMCID: PMC6763963 DOI: 10.1089/hum.2019.143] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Adeno-associated virus (AAV) vector-mediated gene therapy is currently evaluated as a potential treatment for Crigler–Najjar syndrome (CN) (NCT03466463). Pre-existing immunity to AAV is known to hinder gene transfer efficacy, restricting enrollment of seropositive subjects in ongoing clinical trials. We assessed the prevalence of anti-AAV serotype 8 (AAV8) neutralizing antibodies (NAbs) in subjects affected by CN and investigated the impact of low NAb titers (<1:5) on liver gene transfer efficacy in an in vivo passive immunization model. A total of 49 subjects with a confirmed molecular diagnosis of CN were included in an international multicenter study (NCT02302690). Pre-existing NAbs against AAV8 were detected in 30.6% (15/49) of screened patients and, in the majority of positive cases, cross-reactivity to AAV2 and AAV5 was detected. To investigate the impact of low NAbs on AAV vector-mediated liver transduction efficiency, adult wild-type C57BL/6 mice were passively immunized with pooled human donor-derived immunoglobulins to achieve titers of up to 1:3.16. After immunization, animals were injected with different AAV8 vector preparations. Hepatic vector gene copy number was unaffected by low anti-AAV8 NAb titers when column-purified AAV vector batches containing both full and empty capsids were used. In summary, although pre-existing anti-AAV8 immunity can be found in about a third of subjects affected by CN, low anti-AAV8 NAb titers are less likely to affect liver transduction efficiency when using AAV vector preparations manufactured to contain both full and empty capsids. These findings have implications for the design of liver gene transfer clinical trials and for the definition of inclusion criteria related to seropositivity of potential participants.
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Affiliation(s)
- Sem J Aronson
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | | | | | - Aurélie Hubert
- Department of Hereditary Diseases of Hepatic Metabolism, Hôpital Antoine Béclère, Clamart, France
| | | | | | - Robert J de Knegt
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Norman Junge
- Department of Paediatric Gastroenterology and Hepatology, Hannover Medical School, Hannover, Germany.,Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Ulrich Baumann
- Department of Paediatric Gastroenterology and Hepatology, Hannover Medical School, Hannover, Germany.,Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Angelo Di Giorgio
- Department of Paediatric Hepatology, Gastroenterology and Transplantation, Papa Giovanni XXIII Hospital, Bergamo, Italy
| | - Lorenzo D'Antiga
- Department of Paediatric Hepatology, Gastroenterology and Transplantation, Papa Giovanni XXIII Hospital, Bergamo, Italy
| | - Virginia M Ginocchio
- Telethon Institute of Genetics & Medicine (TIGEM), Pozzuoli, Italy.,Department of Translational Medicine, Federico II University of Naples, Naples, Italy
| | - Nicola Brunetti-Pierri
- Telethon Institute of Genetics & Medicine (TIGEM), Pozzuoli, Italy.,Department of Translational Medicine, Federico II University of Naples, Naples, Italy
| | - Philippe Labrune
- Department of Hereditary Diseases of Hepatic Metabolism, Hôpital Antoine Béclère, Clamart, France
| | - Ulrich Beuers
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Piter J Bosma
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
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19
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Meixiong J, Vasavda C, Green D, Zheng Q, Qi L, Kwatra SG, Hamilton JP, Snyder SH, Dong X. Identification of a bilirubin receptor that may mediate a component of cholestatic itch. eLife 2019; 8:44116. [PMID: 30657454 PMCID: PMC6368403 DOI: 10.7554/elife.44116] [Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Accepted: 01/17/2019] [Indexed: 12/31/2022] Open
Abstract
Various pathologic conditions result in jaundice, a yellowing of the skin due to a buildup of bilirubin. Patients with jaundice commonly report experiencing an intense non-histaminergic itch. Despite this association, the pruritogenic capacity of bilirubin itself has not been described, and no bilirubin receptor has been identified. Here, we demonstrate that pathophysiologic levels of bilirubin excite peripheral itch sensory neurons and elicit pruritus through MRGPRs, a family of G-protein coupled receptors expressed in primary sensory neurons. Bilirubin binds and activates two MRGPRs, mouse MRGPRA1 and human MRGPRX4. In two mouse models of pathologic hyperbilirubinemia, we show that genetic deletion of either Mrgpra1 or Blvra, the gene that encodes the bilirubin-producing enzyme biliverdin reductase, attenuates itch. Similarly, plasma isolated from hyperbilirubinemic patients evoked itch in wild-type animals but not Mrgpra1-/- animals. Removing bilirubin decreased the pruritogenic capacity of patient plasma. Based on these data, targeting MRGPRs is a promising strategy for alleviating jaundice-associated itch. Jaundice causes the skin to yellow as a result of a build-up of a pigment called bilirubin. Normally, bilirubin is made in the liver and removed from the body in digestive fluid called bile, but people with liver or gallbladder problems may end up with too much bilirubin that accumulates in their blood and skin. One side effect of jaundice is intense and uncontrollable itching. Researchers are not sure what causes this itching, and there are few treatments that help to relieve it. At the molecular level, itching sensations occur when compounds bind to particular receptors on the surface of nerve cells. One family of receptors that can trigger itch is called the Mas-related G-protein Coupled Receptor (MRGPR). Could one of these receptors trigger jaundice-related itching? Now, Meixiong, Vasavda et al. show that bilirubin binds to and activates MRGPRs to cause itch in mice. Whereas injecting bilirubin into normal mice causes them to scratch, mice that have been genetically engineered to lack MRGPRs do not itch when their own bilirubin levels rise, or when they are injected with bilirubin or with plasma from patients who experience jaundice-related itching. Furthermore, removing bilirubin from the plasma of patients before it was injected into normal mice reduced the amount of itching that the mice felt. Overall, the results reported by Meixiong, Vasavda et al. suggest that drugs that prevent bilirubin from attaching to MRGPRs might help to alleviate jaundice-related itching. However, researchers must first verify that bilirubin interacts with MRGPRs in people to cause itch. If bilirubin causes itch in people like in mice, scientists could then evaluate existing drugs or make new ones to prevent bilirubin from attaching to the MRGPRs.
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Affiliation(s)
- James Meixiong
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States
| | - Chirag Vasavda
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States
| | - Dustin Green
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States
| | - Qin Zheng
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States
| | - Lijun Qi
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States
| | - Shawn G Kwatra
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, United States
| | - James P Hamilton
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States
| | - Solomon H Snyder
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States.,Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, United States.,Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, United States
| | - Xinzhong Dong
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States.,Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, United States.,Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, United States.,Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, United States
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20
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Collaud F, Bortolussi G, Guianvarc'h L, Aronson SJ, Bordet T, Veron P, Charles S, Vidal P, Sola MS, Rundwasser S, Dufour DG, Lacoste F, Luc C, Wittenberghe LV, Martin S, Le Bec C, Bosma PJ, Muro AF, Ronzitti G, Hebben M, Mingozzi F. Preclinical Development of an AAV8-hUGT1A1 Vector for the Treatment of Crigler-Najjar Syndrome. MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT 2018; 12:157-174. [PMID: 30705921 PMCID: PMC6348934 DOI: 10.1016/j.omtm.2018.12.011] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Accepted: 12/26/2018] [Indexed: 12/12/2022]
Abstract
Adeno-associated viruses (AAVs) are among the most efficient vectors for liver gene therapy. Results obtained in the first hemophilia clinical trials demonstrated the long-term efficacy of this approach in humans, showing efficient targeting of hepatocytes with both self-complementary (sc) and single-stranded (ss) AAV vectors. However, to support clinical development of AAV-based gene therapies, efficient and scalable production processes are needed. In an effort to translate to the clinic an approach of AAV-mediated liver gene transfer to treat Crigler-Najjar (CN) syndrome, we developed an (ss)AAV8 vector carrying the human UDP-glucuronosyltransferase family 1-member A1 (hUGT1A1) transgene under the control of a liver-specific promoter. We compared our construct with similar (sc)AAV8 vectors expressing hUGT1A1, showing comparable potency in vitro and in vivo. Conversely, (ss)AAV8-hUGT1A1 vectors showed superior yields and product homogeneity compared with their (sc) counterpart. We then focused our efforts in the scale-up of a manufacturing process of the clinical product (ss)AAV8-hUGT1A1 based on the triple transfection of HEK293 cells grown in suspension. Large-scale production of this vector had characteristics identical to those of small-scale vectors produced in adherent cells. Preclinical studies in animal models of the disease and a good laboratory practice (GLP) toxicology-biodistribution study were also conducted using large-scale preparations of vectors. These studies demonstrated long-term safety and efficacy of gene transfer with (ss)AAV8-hUGT1A1 in relevant animal models of the disease, thus supporting the clinical translation of this gene therapy approach for the treatment of CN syndrome.
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Affiliation(s)
- Fanny Collaud
- INTEGRARE, Genethon, INSERM, Univ. Evry, Université Paris-Saclay, 91002 Evry, France
| | - Giulia Bortolussi
- International Center for Genetic Engineering and Biotechnology, 34149 Trieste, Italy
| | - Laurence Guianvarc'h
- INTEGRARE, Genethon, INSERM, Univ. Evry, Université Paris-Saclay, 91002 Evry, France
| | - Sem J Aronson
- Amsterdam UMC, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, AG&M, 1105 BK Amsterdam, the Netherlands
| | | | - Philippe Veron
- INTEGRARE, Genethon, INSERM, Univ. Evry, Université Paris-Saclay, 91002 Evry, France
| | - Severine Charles
- INTEGRARE, Genethon, INSERM, Univ. Evry, Université Paris-Saclay, 91002 Evry, France
| | - Patrice Vidal
- INTEGRARE, Genethon, INSERM, Univ. Evry, Université Paris-Saclay, 91002 Evry, France
| | - Marcelo Simon Sola
- INTEGRARE, Genethon, INSERM, Univ. Evry, Université Paris-Saclay, 91002 Evry, France
| | - Stephanie Rundwasser
- INTEGRARE, Genethon, INSERM, Univ. Evry, Université Paris-Saclay, 91002 Evry, France
| | - Delphine G Dufour
- INTEGRARE, Genethon, INSERM, Univ. Evry, Université Paris-Saclay, 91002 Evry, France
| | - Florence Lacoste
- INTEGRARE, Genethon, INSERM, Univ. Evry, Université Paris-Saclay, 91002 Evry, France
| | - Cyril Luc
- INTEGRARE, Genethon, INSERM, Univ. Evry, Université Paris-Saclay, 91002 Evry, France
| | | | - Samia Martin
- INTEGRARE, Genethon, INSERM, Univ. Evry, Université Paris-Saclay, 91002 Evry, France
| | - Christine Le Bec
- INTEGRARE, Genethon, INSERM, Univ. Evry, Université Paris-Saclay, 91002 Evry, France
| | - Piter J Bosma
- Amsterdam UMC, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, AG&M, 1105 BK Amsterdam, the Netherlands
| | - Andres F Muro
- International Center for Genetic Engineering and Biotechnology, 34149 Trieste, Italy
| | - Giuseppe Ronzitti
- INTEGRARE, Genethon, INSERM, Univ. Evry, Université Paris-Saclay, 91002 Evry, France
| | - Matthias Hebben
- INTEGRARE, Genethon, INSERM, Univ. Evry, Université Paris-Saclay, 91002 Evry, France
| | - Federico Mingozzi
- INTEGRARE, Genethon, INSERM, Univ. Evry, Université Paris-Saclay, 91002 Evry, France
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21
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Bortolussi G, Muro AF. Advances in understanding disease mechanisms and potential treatments for Crigler–Najjar syndrome. Expert Opin Orphan Drugs 2018. [DOI: 10.1080/21678707.2018.1495558] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Giulia Bortolussi
- Mouse Molecular Genetics Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy
| | - Andrés Fernando Muro
- Mouse Molecular Genetics Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy
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Greig JA, Nordin JM, Draper C, Bell P, Wilson JM. AAV8 Gene Therapy Rescues the Newborn Phenotype of a Mouse Model of Crigler–Najjar. Hum Gene Ther 2018; 29:763-770. [DOI: 10.1089/hum.2017.185] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Affiliation(s)
- Jenny A. Greig
- Gene Therapy Program, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Jayme M.L. Nordin
- Gene Therapy Program, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Christine Draper
- Gene Therapy Program, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Peter Bell
- Gene Therapy Program, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - James M. Wilson
- Gene Therapy Program, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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Apgar JF, Tang JP, Singh P, Balasubramanian N, Burke J, Hodges MR, Lasaro MA, Lin L, Millard BL, Moore K, Jun LS, Sobolov S, Wilkins AK, Gao X. Quantitative Systems Pharmacology Model of hUGT1A1-modRNA Encoding for the UGT1A1 Enzyme to Treat Crigler-Najjar Syndrome Type 1. CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY 2018; 7:404-412. [PMID: 29637732 PMCID: PMC6391595 DOI: 10.1002/psp4.12301] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Revised: 03/19/2018] [Accepted: 03/21/2018] [Indexed: 12/15/2022]
Abstract
Crigler‐Najjar syndrome type 1 (CN1) is an autosomal recessive disease caused by a marked decrease in uridine‐diphosphate‐glucuronosyltransferase (UGT1A1) enzyme activity. Delivery of hUGT1A1‐modRNA (a modified messenger RNA encoding for UGT1A1) as a lipid nanoparticle is anticipated to restore hepatic expression of UGT1A1, allowing normal glucuronidation and clearance of bilirubin in patients. To support translation from preclinical to clinical studies, and first‐in‐human studies, a quantitative systems pharmacology (QSP) model was developed. The QSP model was calibrated to plasma and liver mRNA, and total serum bilirubin in Gunn rats, an animal model of CN1. This QSP model adequately captured the observed plasma and liver biomarker behavior across a range of doses and dose regimens in Gunn rats. First‐in‐human dose projections made using the translated model indicated that 0.5 mg/kg Q4W dose should provide a clinically meaningful and sustained reduction of >5 mg/dL in total bilirubin levels.
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Affiliation(s)
| | - Jian-Ping Tang
- Alexion Pharmaceuticals, Inc., New Haven, Connecticut, USA
| | - Pratap Singh
- Alexion Pharmaceuticals, Inc., New Haven, Connecticut, USA
| | | | - John Burke
- Applied BioMath, Lincoln, Massachusetts, USA
| | | | | | - Lin Lin
- Applied BioMath, Lincoln, Massachusetts, USA
| | | | - Kristi Moore
- Alexion Pharmaceuticals, Inc., New Haven, Connecticut, USA
| | - Lucy S Jun
- Alexion Pharmaceuticals, Inc., New Haven, Connecticut, USA
| | - Susan Sobolov
- Alexion Pharmaceuticals, Inc., New Haven, Connecticut, USA
| | | | - Xiang Gao
- Alexion Pharmaceuticals, Inc., New Haven, Connecticut, USA
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Abstract
BACKGROUND Crigler-Najjar syndrome type I (CNI) arises from biallelic variants of UGT1A1 that abrogate uridine diphosphate glucuronosyltransferase (UGT1A1) activity resulting in unconjugated hyperbilirubinemia. Historically, liver parenchyma in CNI was considered structurally and histologically normal. Recent review of CNI liver explants revealed fibrosis. Our aim was to investigate the association between hepatic histology and disease phenotype in CNI. METHODS We extracted data from the medical record at the time of liver transplant from 22 patients with CNI at the Children's Hospital of Pittsburgh, and reviewed explant histology. Continuous data were normally distributed, are presented as mean (±1 SD), and analyzed using two-tailed Student t-test. Categorical data were analyzed using the Chi-square test. RESULTS Both alanine transaminase (ALT; mean 87.4 IU/L) and aspartate transaminase (AST; mean 54.6 IU/L) were elevated. Nine (41%) of 22 explants had significant fibrosis. Pericentral (n = 5), periportal (n = 2), and mixed (n = 2) patterns of fibrosis occurred. A significant difference in mean age of subjects with fibrotic versus non-fibrotic livers (16.1 years vs 10.5 years; P = 0.02) was seen. There were no indices of synthetic liver dysfunction or portal hypertension. Neither a history of gallstone disease nor excess weight appeared to contribute to the development of fibrosis. CONCLUSIONS For the first time, we report a 41% prevalence of clinically silent, yet histologically significant fibrosis among subjects with Crigler-Najjar type 1. Risk for fibrosis appears to accrue with time, indicating that earlier intervention may be prudent whenever considering alternative treatments such as hepatocyte transplant, auxiliary liver transplant, or viral gene therapy.
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Quaglia A, Roberts EA, Torbenson M. Developmental and Inherited Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2018:111-274. [DOI: 10.1016/b978-0-7020-6697-9.00003-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Kumar P, Sasmal G, Gupta S, Saxena R, Kohli S. Crigler Najjar Syndrome Type 2 (CNS Type 2): An Unwonted Cause of Jaundice in Adults. J Clin Diagn Res 2017; 11:OD05-OD06. [PMID: 28892962 DOI: 10.7860/jcdr/2017/28195.10221] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Accepted: 05/31/2017] [Indexed: 11/24/2022]
Abstract
Crigler Najjar Syndrome (CNS) Type 2 is an uncommon genetic disorder characterised by non-haemolytic unconjugated hyperbilirubinemia. It is caused by mutations in the UGT1A1 gene which codes for the enzyme uridine diphosphate glucoronosyl transferase- 1, required for the conjugation and further excretion of bilirubin from the body. Affected individuals are usually asymptomatic apart from the jaundice and investigations reveal isolated indirect hyperbilirubinemia. It can be conveniently diagnosed by evaluating the response to phenobarbitone in terms of fall in bilirubin levels. Genetic testing of the UGT1A1 gene for mutations is the diagnostic clincher. However, case reports documenting the genetic mutational analysis are sparse. We report one such rare case.
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Affiliation(s)
- Prabhat Kumar
- Senior Resident, Department of General Medicine, Dr. Ram Manohar Lohia Hospital, New Delhi, India
| | - Gargi Sasmal
- Postgraduate Student, Department of General Medicine, Dr. Ram Manohar Lohia Hospital, New Delhi, India
| | - Shreya Gupta
- Postgraduate Student, Department of General Medicine, Dr. Ram Manohar Lohia Hospital, New Delhi, India
| | - Renu Saxena
- Consultant, Department of Genetic Medicine, Sir Ganga Ram Hospital, New Delhi, India
| | - Sudha Kohli
- Consultant, Department of Genetic Medicine, Sir Ganga Ram Hospital, New Delhi, India
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van Dijk R, Aronson SJ, de Waart DR, van de Graaf SF, Duijst S, Seppen J, Elferink RO, Beuers U, Bosma PJ. Biliverdin Reductase inhibitors did not improve severe unconjugated hyperbilirubinemia in vivo. Sci Rep 2017; 7:1646. [PMID: 28490767 PMCID: PMC5431759 DOI: 10.1038/s41598-017-01602-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Accepted: 03/30/2017] [Indexed: 12/31/2022] Open
Abstract
We aimed to identify potent biliverdin reductase (BVRA) inhibitors as a novel concept for the treatment of severe unconjugated hyperbilirubinemia. 1280 FDA-approved compounds were screened in vitro for their ability to inhibit human and rat BVRA activity and 26 compounds were identified as BVRA inhibitors. Montelukast and Disulfiram were selected as potentially clinically applicable drugs and tested to reduce serum unconjugated bilirubin (UCB) levels in the Ugt1a1-deficient rat, a model for chronic unconjugated hyperbilirubinemia. Oral administration of Disulfiram was toxic in the Ugt1a1-deficient rat (weight loss, transaminase elevation). Oral Montelukast administration led to low serum concentrations and did not alter serum UCB levels. Intraperitoneal injections of Montelukast resulted in concentrations up to 110 μmol/L in serum and 400 μmol/L in the liver. Still, serum UCB levels remained unaltered. This first study on biliverdin reductase inhibition as a novel concept for treatment of unconjugated hyperbilirubinemia identified putative in vitro BVRA inhibitors. Montelukast, the clinically most suitable inhibitor, did not result in reduction of serum UCB in the Ugt1a1-deficient rat. The proposed treatment strategy will not result in amelioration of severe unconjugated hyperbilirubinemia in humans without the identification or development of more potent BVRA inhibitors.
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Affiliation(s)
- Remco van Dijk
- Tytgat Institute for Liver and Intestinal Research & Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Sem J Aronson
- Tytgat Institute for Liver and Intestinal Research & Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Dirk R de Waart
- Tytgat Institute for Liver and Intestinal Research & Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Stan F van de Graaf
- Tytgat Institute for Liver and Intestinal Research & Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Suzanne Duijst
- Tytgat Institute for Liver and Intestinal Research & Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Jurgen Seppen
- Tytgat Institute for Liver and Intestinal Research & Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Ronald Oude Elferink
- Tytgat Institute for Liver and Intestinal Research & Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Ulrich Beuers
- Tytgat Institute for Liver and Intestinal Research & Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Piter J Bosma
- Tytgat Institute for Liver and Intestinal Research & Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
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A translationally optimized AAV-UGT1A1 vector drives safe and long-lasting correction of Crigler-Najjar syndrome. MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT 2016; 3:16049. [PMID: 27722180 PMCID: PMC5052023 DOI: 10.1038/mtm.2016.49] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/22/2016] [Revised: 06/03/2016] [Accepted: 06/03/2016] [Indexed: 12/22/2022]
Abstract
Crigler-Najjar syndrome is a severe metabolic disease of the liver due to a
reduced activity of the UDP Glucuronosyltransferase 1A1 (UGT1A1) enzyme. In an
effort to translate to the clinic an adeno-associated virus vector mediated
liver gene transfer approach to treat Crigler-Najjar syndrome, we developed and
optimized a vector expressing the UGT1A1 transgene. For this purpose, we
designed and tested in vitro and in vivo multiple
codon-optimized UGT1A1 transgene cDNAs. We also optimized noncoding sequences in
the transgene expression cassette. Our results indicate that transgene
codon-optimization is a strategy that can improve efficacy of gene transfer but
needs to be carefully tested in vitro and in vivo.
Additionally, while inclusion of introns can enhance gene expression,
optimization of these introns, and in particular removal of cryptic ATGs and
splice sites, is an important maneuver to enhance safety and efficacy of gene
transfer. Finally, using a translationally optimized adeno-associated virus
vector expressing the UGT1A1 transgene, we demonstrated rescue of the phenotype
of Crigler-Najjar syndrome in two animal models of the disease, Gunn rats and
Ugt1a1-/- mice. We also showed long-term (>1 year)
correction of the disease in Gunn rats. These results support further
translation of the approach to humans.
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Fernandes SR, Moura CM, Rodrigues B, Correia LA, Cortez-Pinto H, Velosa J. Acute cholangitis in an old patient with Crigler-Najjar syndrome type II - a case report. BMC Gastroenterol 2016; 16:33. [PMID: 26968162 PMCID: PMC4788912 DOI: 10.1186/s12876-016-0449-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2015] [Accepted: 03/07/2016] [Indexed: 12/27/2022] Open
Abstract
Background Crigler-Najjar syndrome (CN) is a very rare genetic disorder characterized by an inability to conjugate bilirubin. Contrary to CN type I, patients with CN II exhibit residual capacity to conjugate bilirubin and may present a normal life expectancy. Case presentation We report an unusual late diagnosis of CN type II in an 80-year-old female admitted with severe acute cholangitis. While the patient present typical clinical and radiologic signs of bile duct obstruction and cholangitis, her blood analysis showed severe unconjugated hyperbilirubinemia. Endoscopic retrograde cholangiopancreatography confirmed the diagnosis and allowed therapeutic intervention. The anatomopathologic examination of her gallbladder following cholecystectomy showed signs of chronic cholecystitis. Conclusion The risk of gallstone disease may be increased in patients with CN syndrome. While unusual, we alert to this curious and potential life-threatening presentation.
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Affiliation(s)
- Samuel Raimundo Fernandes
- Serviço de Gastrenterologia e Hepatologia, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Avenida Professor Egas Moniz, Lisboa, 1649-035, Portugal. .,, Avenida Tomás Fonseca n° 36, 13, Lisbon, B 1600-275, Portugal.
| | - Carlos Miguel Moura
- Serviço de Gastrenterologia e Hepatologia, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Avenida Professor Egas Moniz, Lisboa, 1649-035, Portugal
| | - Beatriz Rodrigues
- Serviço de Gastrenterologia e Hepatologia, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Avenida Professor Egas Moniz, Lisboa, 1649-035, Portugal
| | - Luís Araújo Correia
- Serviço de Gastrenterologia e Hepatologia, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Avenida Professor Egas Moniz, Lisboa, 1649-035, Portugal
| | - Helena Cortez-Pinto
- Serviço de Gastrenterologia e Hepatologia, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Avenida Professor Egas Moniz, Lisboa, 1649-035, Portugal
| | - José Velosa
- Serviço de Gastrenterologia e Hepatologia, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Avenida Professor Egas Moniz, Lisboa, 1649-035, Portugal
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Memon N, Weinberger BI, Hegyi T, Aleksunes LM. Inherited disorders of bilirubin clearance. Pediatr Res 2016; 79:378-86. [PMID: 26595536 PMCID: PMC4821713 DOI: 10.1038/pr.2015.247] [Citation(s) in RCA: 105] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2015] [Accepted: 08/31/2015] [Indexed: 01/01/2023]
Abstract
Inherited disorders of hyperbilirubinemia may be caused by increased bilirubin production or decreased bilirubin clearance. Reduced hepatic bilirubin clearance can be due to defective (i) unconjugated bilirubin uptake and intrahepatic storage, (ii) conjugation of glucuronic acid to bilirubin (e.g., Gilbert syndrome, Crigler-Najjar syndrome, Lucey-Driscoll syndrome, breast milk jaundice), (iii) bilirubin excretion into bile (Dubin-Johnson syndrome), or (iv) conjugated bilirubin re-uptake (Rotor syndrome). In this review, the molecular mechanisms and clinical manifestations of these conditions are described, as well as current approaches to diagnosis and therapy.
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Affiliation(s)
- Naureen Memon
- Department of Pediatrics, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA,Corresponding author: Naureen Memon, M.D., Department of Pediatrics, Rutgers Robert Wood Johnson Medical School, 1 Robert Wood Johnson Place, MEB 396, New Brunswick, NJ, 08901 USA, Phone: (732) 235-5599, Fax: (732) 235-5668,
| | - Barry I Weinberger
- Department of Pediatrics, Cohen Children’s Medical Center of New York, New Hyde Park, NY, USA
| | - Thomas Hegyi
- Department of Pediatrics, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Lauren M Aleksunes
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ, USA
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Bai J, Qu Y, Cao Y, Li Y, Zhang W, Jin Y, Wang H, Song F. X-linked ichthyosis and Crigler-Najjar syndrome I: Coexistence in a male patient with two copy number variable regions of 2q37.1 and Xp22.3. Mol Med Rep 2015; 13:1135-40. [PMID: 26676689 PMCID: PMC4732863 DOI: 10.3892/mmr.2015.4674] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2015] [Accepted: 11/18/2015] [Indexed: 11/06/2022] Open
Abstract
X-linked ichthyosis (XLI) is an X-linked recessive skin disorder generally restricted to males, which arises from mutations in the steroid sulfatase (STS) gene located on Xp22.3. Crigler-Najjar syndrome (CN-I) is a rare autosomal recessive disease caused by the homozygous or compound heterozygous mutations in the UPD-glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) gene on chromosome 2q37. A male patient was referred to the Department of Medical Genetics with of severe icterus and ichthyosis. The patient and his family members underwent genetic tests related to XLI and CN-I. Quantitative polymerase chain reaction on genomic DNA was performed to determine the gene copy number, while single nucleotide polymorphism array analysis was conducted to identify deletion mutations. Family pedigree analysis showed that the patient and his two cousins were all affected by ichthyosis, which was in accordance with the inheritance pattern of an X-linked recessive disease. In addition, the patient's serum bilirubin concentration (>340 mmol/l) was markedly greater than the normal level. The patient presented with kernicterus and phenobarbital treatment was ineffective. The clinical diagnosis of XLI was confirmed molecularly by laboratory evidence of a maternal 1.61 M deletion (including the STS gene) on ChrXp22.31. Coincidentally, the male patient was also confirmed to carry a rare maternal inherited microdeletion (374 Kb) comprising the entire UGT1A1 gene combined with a paternal UGT1A1 mutation (c.1253delT), a causative event of CN-I. To the best of our knowledge, this study reported for the first time the comorbidity of XLI and CN-I in a male patient. The results suggested that co-occurrence of these two recessive diseases in a patient may be incidental.
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Affiliation(s)
- Jinli Bai
- Department of Medical Genetics, Capital Institute of Pediatrics, Beijing 100020, P.R. China
| | - Yujin Qu
- Department of Medical Genetics, Capital Institute of Pediatrics, Beijing 100020, P.R. China
| | - Yanyan Cao
- Department of Medical Genetics, Capital Institute of Pediatrics, Beijing 100020, P.R. China
| | - Yan Li
- Department of Medical Genetics, Capital Institute of Pediatrics, Beijing 100020, P.R. China
| | - Wenhui Zhang
- Department of Medical Genetics, Capital Institute of Pediatrics, Beijing 100020, P.R. China
| | - Yuwei Jin
- Department of Medical Genetics, Capital Institute of Pediatrics, Beijing 100020, P.R. China
| | - Hong Wang
- Department of Medical Genetics, Capital Institute of Pediatrics, Beijing 100020, P.R. China
| | - Fang Song
- Department of Medical Genetics, Capital Institute of Pediatrics, Beijing 100020, P.R. China
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Aronson SJ, Beuers U, Bosma PJ. Progress and challenges in gene therapy for Crigler–Najjar syndrome. Expert Opin Orphan Drugs 2015. [DOI: 10.1517/21678707.2015.1100991] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Polley N, Saha S, Adhikari A, Banerjee S, Darbar S, Das S, Pal SK. Safe and symptomatic medicinal use of surface-functionalized Mn3O4 nanoparticles for hyperbilirubinemia treatment in mice. Nanomedicine (Lond) 2015; 10:2349-63. [DOI: 10.2217/nnm.15.83] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Aim: Testing the potential of citrate-capped Mn3O4 nanoparticles (NPs) as a therapeutic agent for alternative rapid treatment of hyperbilirubinemia through direct removal of bilirubin (BR) from blood in mice. Materials & methods: NPs were synthesized and the mechanism of BR degradation in presence and absence of biological macromolecules were characterized in vitro. To test the in vivo BR degradation ability of NPs, CCl4-intoxicated mice were intraperitoneally injected with NPs. Results: We demonstrated ultrahigh efficacy of the NPs in symptomatic treatment of hyperbilirubinemia for rapid reduction of BR in mice compared with conventional medicine silymarin without any toxicological implications. Conclusion: These findings may pave the way for practical clinical use of the NPs as safe medication of hyperbilirubinemia in human subjects.
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Affiliation(s)
- Nabarun Polley
- Department of Chemical, Biological & Macromolecular Sciences, S N Bose National Centre for Basic Sciences, Block JD, Sector III, Salt Lake, Kolkata 700 098, India
| | - Srimoyee Saha
- Department of Physics, Jadavpur University, 188, Raja Subodh Chandra Mullick Road, Jadavpur, Kolkata 700032, India
| | - Aniruddha Adhikari
- Department of Chemical, Biological & Macromolecular Sciences, S N Bose National Centre for Basic Sciences, Block JD, Sector III, Salt Lake, Kolkata 700 098, India
| | - Somtirtha Banerjee
- Department of Physics, Jadavpur University, 188, Raja Subodh Chandra Mullick Road, Jadavpur, Kolkata 700032, India
| | - Soumendra Darbar
- Research & Development Division, Dey's Medical Stores (Mfg.) Ltd, 62, Bondel Road, Ballygunge, Kolkata 700019, India
| | - Sukhen Das
- Department of Physics, Jadavpur University, 188, Raja Subodh Chandra Mullick Road, Jadavpur, Kolkata 700032, India
| | - Samir Kumar Pal
- Department of Chemical, Biological & Macromolecular Sciences, S N Bose National Centre for Basic Sciences, Block JD, Sector III, Salt Lake, Kolkata 700 098, India
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Maerckx C, Tondreau T, Berardis S, Pelt JV, Najimi M, Sokal E. Human liver stem/progenitor cells decrease serum bilirubin in hyperbilirubinemic Gunn rat. World J Gastroenterol 2014; 20:10553-10563. [PMID: 25132775 PMCID: PMC4130866 DOI: 10.3748/wjg.v20.i30.10553] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2013] [Revised: 02/08/2014] [Accepted: 03/10/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To test the ability of adult-derived human liver stem/progenitor cells (ADHLSC) from large scale cultures to conjugate bilirubin in vitro and in bilirubin conjugation deficient rat.
METHODS: ADHLSC from large scale cultures were tested for their phenotype and for their capacity to conjugate bilirubin in vitro after hepatogenic differentiation. In vivo, Gunn rats [uridine diphosphate-glucuronosyltransferase 1A1 (UGT1A1) deficient animal] were injected with ADHLSC and cryopreserved hepatocytes (positive control). Two, 4, 13 and 27 wk post-transplantation, transplanted Gunn rat bilirubin serum levels were determined by high performance liquid chromatography. Human transplanted cell engraftment was assessed 27 wk post-transplantation using immunohistochemistry and RTqPCR.
RESULTS: Large scale culture conditions do not modify ADHLSC phenotype, ADHLSC were able to specifically conjugate bilirubin. ADHLSC were intraportally injected into Gunn rats and blood UCB was measured at different times post-transplantation, infused-Gunn rats exhibited a metabolic effect 3 mo post-transplantation and maintained over a 6 mo period. ADHLSC engraftment into Gunn rat’s liver was demonstrated by RTqPCR and immunohistochemistry against albumin and UGT1A1.
CONCLUSION: ADHLSC from large scale cultures are efficient in conjugating bilirubin in vitro and in restoring a deficient metabolic function (reducing bilirubin level) in hyperbilirubinemic rats.
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Squires RH, Ng V, Romero R, Ekong U, Hardikar W, Emre S, Mazariegos GV. Evaluation of the pediatric patient for liver transplantation: 2014 practice guideline by the American Association for the Study of Liver Diseases, American Society of Transplantation and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Hepatology 2014; 60:362-98. [PMID: 24782219 DOI: 10.1002/hep.27191] [Citation(s) in RCA: 142] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2014] [Accepted: 04/22/2014] [Indexed: 12/16/2022]
Affiliation(s)
- Robert H Squires
- Department of Pediatrics, University of Pittsburgh School of Medicine; Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA
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Erlinger S, Arias IM, Dhumeaux D. Inherited disorders of bilirubin transport and conjugation: new insights into molecular mechanisms and consequences. Gastroenterology 2014; 146:1625-38. [PMID: 24704527 DOI: 10.1053/j.gastro.2014.03.047] [Citation(s) in RCA: 141] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2013] [Revised: 03/12/2014] [Accepted: 03/23/2014] [Indexed: 12/11/2022]
Abstract
Inherited disorders of bilirubin metabolism might reduce bilirubin uptake by hepatocytes, bilirubin conjugation, or secretion of bilirubin into bile. Reductions in uptake could increase levels of unconjugated or conjugated bilirubin (Rotor syndrome). Defects in bilirubin conjugation could increase levels of unconjugated bilirubin; the effects can be benign and frequent (Gilbert syndrome) or rare but severe, increasing the risk of bilirubin encephalopathy (Crigler-Najjar syndrome). Impairment of bilirubin secretion leads to accumulation of conjugated bilirubin (Dubin-Johnson syndrome). We review the genetic causes and pathophysiology of disorders of bilirubin transport and conjugation as well as clinical and therapeutic aspects. We also discuss the possible mechanisms by which hyperbilirubinemia protects against cardiovascular disease and the metabolic syndrome and the effects of specific genetic variants on drug metabolism and cancer development.
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Affiliation(s)
| | | | - Daniel Dhumeaux
- Henri Mondor Hospital, Créteil, University of Paris-Est, Créteil, France
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Giri A, Goswami N, Sasmal C, Polley N, Majumdar D, Sarkar S, Bandyopadhyay SN, Singha A, Pal SK. Unprecedented catalytic activity of Mn3O4 nanoparticles: potential lead of a sustainable therapeutic agent for hyperbilirubinemia. RSC Adv 2014. [DOI: 10.1039/c3ra45545a] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
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Intrathecal baclofen therapy after liver transplant in a patient with Crigler-Najjar syndrome. PM R 2013; 6:196-8. [PMID: 24365780 DOI: 10.1016/j.pmrj.2013.09.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2013] [Revised: 08/30/2013] [Accepted: 09/03/2013] [Indexed: 11/22/2022]
Abstract
Crigler-Najjar syndrome (CNS) is described as severe infantile, nonhemolytic, unconjugated hyperbilirubinemia and is divided into type I and type II according to the patient's response to phenobarbital treatment. Patients with type I CNS usually require a liver transplant. These patients often have spasticity and dystonia, both of which can be treated with intrathecal baclofen therapy. We present the case of a patient with CNS type I who underwent a liver transplant followed years later by intrathecal baclofen therapy. To our knowledge, this article provides the first report of a patient with CNS being treated for dystonia with an intrathecal baclofen pump. Despite his complicated history, this patient has remained medically stable after both interventions.
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Fagiuoli S, Daina E, D'Antiga L, Colledan M, Remuzzi G. Monogenic diseases that can be cured by liver transplantation. J Hepatol 2013; 59:595-612. [PMID: 23578885 DOI: 10.1016/j.jhep.2013.04.004] [Citation(s) in RCA: 95] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2012] [Revised: 04/02/2013] [Accepted: 04/02/2013] [Indexed: 02/08/2023]
Abstract
While the prevalence of most diseases caused by single-gene mutations is low and defines them as rare conditions, all together, monogenic diseases account for approximately 10 in every 1000 births according to the World Health Organisation. Orthotopic liver transplantation (LT) could offer a therapeutic option in monogenic diseases in two ways: by substituting for an injured liver or by supplying a tissue that can replace a mutant protein. In this respect, LT may be regarded as the correction of a disease at the level of the dysfunctional protein. Monogenic diseases that involve the liver represent a heterogeneous group of disorders. In conditions associated with predominant liver parenchymal damage (i.e., genetic cholestatic disorders, Wilson's disease, hereditary hemochromatosis, tyrosinemia, α1 antitrypsin deficiency), hepatic complications are the major source of morbidity and LT not only replaces a dysfunctional liver but also corrects the genetic defect and effectively cures the disease. A second group includes liver-based genetic disorders characterised by an architecturally near-normal liver (urea cycle disorders, Crigler-Najjar syndrome, familial amyloid polyneuropathy, primary hyperoxaluria type 1, atypical haemolytic uremic syndrome-1). In these defects, extrahepatic complications are the main source of morbidity and mortality while liver function is relatively preserved. Combined transplantation of other organs may be required, and other surgical techniques, such as domino and auxiliary liver transplantation, have been attempted. In a third group of monogenic diseases, the underlying genetic defect is expressed at a systemic level and liver involvement is just one of the clinical manifestations. In these conditions, LT might only be partially curative since the abnormal phenotype is maintained by extrahepatic synthesis of the toxic metabolites (i.e., methylmalonic acidemia, propionic acidemia). This review focuses on principles of diagnosis, management and LT results in both paediatric and adult populations of selected liver-based monogenic diseases, which represent examples of different transplantation strategies, driven by the understanding of the expression of the underlying genetic defect.
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Affiliation(s)
- Stefano Fagiuoli
- Gastroenterology and Transplant Hepatology, Ospedale Papa Giovanni XXIII, Bergamo, Italy.
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Cuperus FJC, Schreuder AB, van Imhoff DE, Vitek L, Vanikova J, Konickova R, Ahlfors CE, Hulzebos CV, Verkade HJ. Beyond plasma bilirubin: the effects of phototherapy and albumin on brain bilirubin levels in Gunn rats. J Hepatol 2013; 58:134-40. [PMID: 22922094 DOI: 10.1016/j.jhep.2012.08.011] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2012] [Revised: 08/09/2012] [Accepted: 08/13/2012] [Indexed: 12/04/2022]
Abstract
BACKGROUND & AIMS Severe unconjugated hyperbilirubinemia, as occurs in Crigler-Najjar disease and neonatal jaundice, carries the risk of neurotoxicity. This neurotoxicity is related to the increased passage of free bilirubin (UCB(free)), the fraction of bilirubin that is not bound to plasma proteins, into the brain. We hypothesized that albumin treatment would lower the UCB(free) fraction, and thus decrease bilirubin accumulation in the brain. METHODS We treated chronic (e.g., as a model for Crigler-Najjar disease) and acute hemolytic (e.g., as a model for neonatal jaundice) moderate hyperbilirubinemic Gunn rats with phototherapy, human serum albumin (HSA) or phototherapy+HSA. RESULTS In the chronic model, adjunct HSA increased the efficacy of phototherapy; it decreased plasma UCB(free) and brain bilirubin by 88% and 67%, respectively (p<0.001). In the acute model, adjunct HSA also increased the efficacy of phototherapy; it decreased plasma UCB(free) by 76% (p<0.001) and completely prevented the hemolysis-induced deposition of bilirubin in the brain. Phototherapy alone failed to prevent the deposition of bilirubin in the brain during acute hemolytic jaundice. CONCLUSIONS We showed that adjunct HSA treatment decreases brain bilirubin levels in phototherapy-treated Gunn rats. We hypothesize that HSA decreases these levels by lowering UCB(free) in the plasma. Our results support the feasibility of adjunct albumin treatment in patients with Crigler-Najjar disease or neonatal jaundice.
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Affiliation(s)
- Frans J C Cuperus
- Pediatric Gastroenterology and Hepatology, Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, Beatrix Children's Hospital - University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
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Abstract
Initially hailed as the ultimate solution to organ failure, engineering of vascularized tissues such as the liver has stalled because of the need for a well-structured circulatory system that can maintain the cells seeded inside the construct. A new approach has evolved to overcome this obstacle. Whole-organ decellularization is a method that retains most of the native vascular structures of the organ, providing microcirculatory support and structure, which can be anastomosed with the recipient circulation. The technique was first applied to the heart and then adapted for the liver. Several studies have shown that cells can be eliminated, the extracellular matrix and vasculature are reasonably preserved and, after repopulation with hepatocytes, these grafts can perform hepatic functions in vitro and in vivo. Progress is rapidly being made as researchers are addressing several key challenges to whole-organ tissue engineering, such as ensuring correct cell distribution, nonparenchymal cell seeding, blood compatibility, immunological concerns, and the source of cells and matrices.
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Tu ZH, Shang DS, Jiang JC, Zhang W, Zhang M, Wang WL, Lou HY, Zheng SS. Liver transplantation in Crigler-Najjar syndrome type I disease. Hepatobiliary Pancreat Dis Int 2012; 11:545-8. [PMID: 23060403 DOI: 10.1016/s1499-3872(12)60222-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Crigler-Najjar syndrome type I (CNS I) is a very rare autosomal recessive inherited disease that liver transplantation can properly deal with. METHODS We present one case of an 18-month-old child with CNS I diagnosed by clinical findings and genetic detecting. LTx was performed 5 days after kernicterus broke out and neurological symptoms were successfully reversed. RESULT Magnetic resonance imaging and magnetic resonance spectroscopy showed encouraging results that brain pathology had a trend to return to normal in 1-year follow-up, combined with electroencephalogram and motor development estimate studies. CONCLUSIONS Liver transplantation can cure CNS I with reversible neurological symptoms to some extent in time. Magnetic resonance spectroscopy may be a future option of predicting brain conditions and selecting suitable patients with CNS I for transplantation.
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Affiliation(s)
- Zhen-Hua Tu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health & Key Laboratory of Organ Transplantation of Zhejiang Province, Hangzhou 310003, China
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Montenegro-Miranda PS, Sneitz N, de Waart DR, ten Bloemendaal L, Duijst S, de Knegt RJ, Beuers U, Finel M, Bosma PJ. Ezetimibe: A biomarker for efficacy of liver directed UGT1A1 gene therapy for inherited hyperbilirubinemia. Biochim Biophys Acta Mol Basis Dis 2012; 1822:1223-9. [DOI: 10.1016/j.bbadis.2012.04.013] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2012] [Revised: 03/27/2012] [Accepted: 04/17/2012] [Indexed: 11/24/2022]
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Graft fibrosis and recipient survival in postorthotopic liver transplant nonalcoholic fatty liver disease. EGYPTIAN LIVER JOURNAL 2012. [DOI: 10.1097/01.elx.0000407755.75559.9f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
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Cuperus FJC, Iemhoff AA, Verkade HJ. Combined treatment strategies for unconjugated hyperbilirubinemia in Gunn rats. Pediatr Res 2011; 70:560-5. [PMID: 21857383 DOI: 10.1203/pdr.0b013e31823240bc] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
We recently demonstrated that acceleration of the gastrointestinal transit by polyethylene glycol (PEG) treats unconjugated hyperbilirubinemia in jaundiced Gunn rats. It is unclear whether acceleration of gastrointestinal transit also (partly) underlies the therapeutic effects of established hypobilirubinemic treatments or whether PEG cotreatment might enhance these effects. We treated Gunn rats with phototherapy (17 μW/cm2/nm), orlistat (200 mg/kg chow), ursodeoxycholate (5 g/kg chow), or calcium phosphate (CaP) (20 g/kg chow) either as single treatment or in combination with PEG. Three weeks of phototherapy, orlistat, ursodeoxycholic acid, or CaP treatment decreased plasma unconjugated bilirubin (UCB) levels by 47, 27, 28, and 45%, respectively (each p < 0.001), without a significant impact on gastrointestinal transit time. PEG cotreatment accelerated the gastrointestinal transit in all treatment groups, which resulted in an additive hypobilirubinemic effect of -20% and -26% (final plasma UCB -67 and -53%, respectively) in phototherapy- and orlistat-treated animals. PEG cotreatment did not enhance the hypobilirubinemic effect of ursodeoxycholic acid or CaP. We conclude that phototherapy, orlistat, ursodoxycholic acid, and CaP do not exert their hypobilirubinemic effect via acceleration of the gastrointestinal transit. PEG cotreatment enhanced the hypobilirubinemic effects of phototherapy and of orlistat treatment. Current results support a clinical trial to evaluate PEG cotreatment during phototherapy.
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Affiliation(s)
- Frans J C Cuperus
- Department of Pediatrics, Beatrix Children's Hospital-University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands
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Shneider BL, Vockley J, Mazariegos GV. Trading places: liver transplantation as a treatment, not a cure, for metabolic liver disease. Liver Transpl 2011; 17:628-30. [PMID: 21384526 DOI: 10.1002/lt.22293] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Abstract
Elevation of the serum bilirubin level is a common, if not universal, finding during the first week of life. This can be a transient phenomenon that resolves spontaneously or can signify a serious or even life-threatening condition. There are many causes of hyperbilirubinemia and related therapeutic and prognostic implications. The diseases in which there is a primary disorder of the metabolism of bilirubin will be reviewed regarding their clinical presentation, pathophysiology, diagnosis, and treatment. These disorders-Gilbert's syndrome and Crigler-Najjar Syndrome-both involve abnormalities in bilirubin conjugation secondary to deficiency of bilirubin uridine diphosphate glucuronosyltransferase. The purpose of this article is to review the current understanding of the genetic polymorphisms that result in these diseases and discuss recent advances in diagnosis and treatment.
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Darwish AA, McKiernan P, Chardot C. Paediatric liver transplantation for metabolic disorders. Part 1: Liver-based metabolic disorders without liver lesions. Clin Res Hepatol Gastroenterol 2011; 35:194-203. [PMID: 21376697 DOI: 10.1016/j.clinre.2011.01.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Liver-based metabolic disorders account for 10 to 15% of the indications for paediatric liver transplantation. In the last three decades, important progress has been made in the understanding of these diseases, and new therapies have emerged. Concomitantly, medical and surgical innovations have lead to improved results of paediatric liver transplantation, patient survival nowadays exceeding 80% 10-year after surgery with close to normal quality of life in most survivors. This review is a practical update on medical therapy, indications and results of liver transplantation, and potential future therapies, for the main liver-based metabolic disorders in which paediatric liver transplantation may be considered. Part 1 focuses on metabolic based liver disorders without liver lesions, and part 2 on metabolic liver diseases with liver lesions.
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Affiliation(s)
- Ahmed A Darwish
- University of Geneva Children's hospital, Paediatric Surgery Unit, Geneva, Switzerland
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Dimmock D, Brunetti-Pierri N, Palmer DJ, Beaudet AL, Ng P. Correction of hyperbilirubinemia in gunn rats using clinically relevant low doses of helper-dependent adenoviral vectors. Hum Gene Ther 2011; 22:483-8. [PMID: 20973621 DOI: 10.1089/hum.2010.167] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Crigler-Najjar syndrome type I is a severe inborn error of bilirubin metabolism caused by a complete deficiency of uridine diphospho-glucuronosyl transferase 1A1 (UGT1A1) and results in life-threatening unconjugated hyperbilirubinemia. Lifelong correction of hyperbilirubinemia by liver-directed gene therapy using a helper-dependent adenoviral (HDAd) vector has been previously reported in the Gunn rat, a model of Crigler-Najjar syndrome, but was only achieved using high doses (≥ 3 × 10(12) viral particles [vp]/kg), which are likely to elicit a severe toxic response in humans. Therefore, in this study, we investigate strategies to achieve correction of hyperbilirubinemia in the Gunn rat using clinically relevant low HDAd doses. We have found that correction of hyperbilirubinemia in the Gunn rat can be achieved with a low dose of 5 × 10(11) vp/kg by using an HDAd vector bearing a more potent UGT1A1 expression cassette. Furthermore, by using hydrodynamic injection of the improved HDAd vector, correction of hyperbilirubinemia in the Gunn rat can be achieved using an even lower dose of 5 × 10(10) vp/kg. Although hydrodynamic injection as performed in rats is not acceptable in humans, clinically attractive, minimally invasive methods have been successfully developed to mimic hydrodynamic injection of HDAd vector in non-human primates. Therefore, using an improved expression cassette combined with a more efficient method of vector delivery permits correction of hyperbilirubinemia in the Gunn rat using clinically relevant low HDAd doses and may thus pave the way to clinical application of HDAd vectors for Crigler-Najjar syndrome gene therapy.
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Affiliation(s)
- David Dimmock
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
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