RARE DISEASE
Crigler-Najjar syndrome
Crigler-Najjar syndrome
Crigler-Najjar syndrome
Synonyms: Bilirubin uridinediphosphate glucuronosyltransferase deficiency, Bilirubin-UGT deficiency
Synonyms: Bilirubin uridinediphosphate glucuronosyltransferase deficiency, Bilirubin-UGT deficiency
Synonyms: Bilirubin uridinediphosphate glucuronosyltransferase deficiency, Bilirubin-UGT deficiency
Drug discovery
10
drugs
With orphan designations
Overview
Crigler-Najjar syndrome (CNS) is a rare autosomal recessive disorder caused by UGT1A1 mutations, impairing bilirubin conjugation and leading to severe unconjugated hyperbilirubinemia. Type 1 (CN1) features absent UDP-glucuronosyltransferase activity, requiring aggressive intervention to prevent kernicterus, while type 2 (CN2) retains partial enzyme function, managed with pharmacotherapy. Current treatments include phototherapy, phenobarbital (CN2), and liver transplantation (CN1), with emerging gene therapies under investigation [1][3][6][12].
Therapies
CN1:
Daily phototherapy (≥12 hours) to reduce bilirubin [3][9][15].
Liver transplantation as curative intervention (5-year survival: 81–95%) [3][8][13].
CN2: Phenobarbital to induce residual enzyme activity [3][5][9].
Emerging therapies: AAV-based gene therapy trials (e.g., GNT-0003) and hepatocyte transplantation [8][11][15].
Categories: rare genetic diseases, rare hepatic diseases, rare inborn errors of metabolism, rare transplant-related disorders
Research Papers
419 drug discovery papers about Crigler-Najjar syndrome, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
419 drug discovery papers about Crigler-Najjar syndrome, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-05-29 | Rewriting hepatic fate: emerging gene therapy strategies for liver disease
Several anatomical and physiological features make the liver particularly suitable for gene-based therapeutic strategies, including its extensive vascularization, fenestrated sinusoidal endothelium, and high metabolic capacity. In the past decade, liver-directed gene therapies have evolved from experimental concepts to clinical applications for various inherited and systemic disorders. Adeno-associated viral vectors, lentiviral systems, and lipid nanoparticles are currently the main platforms for delivering therapeutic genes and genome-editing tools to hepatocytes. Genome editing technologies such as CRISPR-Cas nucleases, base editors, and prime editors have enabled more precise modification of endogenous loci. Early clinical studies in disorders like hemophilia, transthyretin amyloidosis, ornithine transcarbamylase deficiency, and Crigler-Najjar syndrome show that partial correction of hepatic gene function can lead to meaningful clinical benefits. However, several challenges hinder broader clinical implementation, including immune responses to viral capsids and nanoparticle components, dose-dependent toxicity, limited packaging capacity of some vectors, and uncertainties about long-term safety and durability, especially in pediatric populations. Efficient and cell-type-specific delivery beyond hepatocytes remains a major challenge, particularly for diseases driven by non-parenchymal cells or malignant transformation. This article discusses recent advancements in delivery technologies and genome editing approaches for liver disease, as well as current translational barriers and emerging strategies aimed at enhancing specificity, durability, and safety. Collectively, these advances suggest that increasingly precise and programmable gene-based interventions may play a central role in future therapies for a broad spectrum of liver diseases.
2026-05-21 | Case Report: Retransplantation for Adult-Onset Bilirubin Encephalopathy After Auxiliary Partial Liver Transplant for Crigler-Najjar Syndrome Type 1 in Childhood.
Crigler-Najjar syndrome (CNS) type 1 is a genetic disorder that leads to severe unconjugated hyperbilirubinemia. Auxiliary partial orthotopic liver transplantation (APOLT) is preferred for metabolic liver diseases as a portion of the native liver is retained. Reported here are details of a 32-year-old male who developed bilirubin encephalopathy due to graft failure 27 years after APOLT performed at 5-year-old for CNS type 1. Initially, the bilirubin level was low, which then gradually increased to 7.3 mg/dL at age 12. At the age of 31, the bilirubin level began to rise rapidly and we submitted a request for deceased donor liver transplantation (DDLT) to the Committee for the Evaluation of Indications for DDLT in Japan. However, that was deemed as not indicated, because unconjugated bilirubin-dominant hyperbilirubinemia alone is generally not considered to cause encephalopathy in adults. Despite the high bilirubin level, the patient remained neurologically asymptomatic until occurrence of acute decompensation. At 32 years old, he was admitted on an emergency basis to our hospital with severe hyperbilirubinemia and neurological symptoms. After managing his general condition with intensive care, DDLT was finally performed, resulting in a drastic resolution of various symptoms. The findings in this case show that bilirubin-induced neurotoxicity in adults may be reversible and indicate that the current liver transplantation criteria used in Japan, which limit eligibility for CNS to pediatric patients, may have contributed to delayed transplantation. Re-evaluation of the transplant eligibility criteria is necessary to allow for a more inclusive approach that encompasses adult patients.
2026-01-09 | Engineering Liver-Specific Promoters: A Comprehensive Review of Design, Mechanisms, and Clinical Applications in Gene Therapy.
The liver is a primary metabolic hub and a pivotal target for gene therapy, owing to its capacity for protein secretion, role in metabolic homeostasis and immune tolerance. Liver-directed gene therapies are used to treat numerous inherited metabolic disorders and coagulation factor deficiencies including hemophilia (A and B), Crigler-Najjar syndrome, mucopolysaccharidoses, phenylketonuria, Fabry, Gaucher, Wilson and Pompe diseases. The efficacy and safety of liver-directed gene therapy rely on the use of strong tissue-specific promoters. To date, there are many different liver-specific promoters used in preclinical and clinical studies, including novel completely synthetic promoters. This review provides a comprehensive analysis of the design, engineering and application of liver-specific promoters. Furthermore, we discuss fundamental principles of gene expression regulation in the liver and the physiological and immunological characteristics that make it a suitable target organ for gene therapy delivery.
2025-12-01 | From Childhood Icterus to Adolescent Gallstones: Clinically Diagnosed Crigler-Najjar Syndrome Type II
From Childhood Icterus to Adolescent Gallstones: Clinically Diagnosed Crigler-Najjar Syndrome Type IIDanish Kumar GoswamiEmail: daniahgoswami34@gmail.com Institute/Affiliation: Department of Internal Medicine, Liaquat University of Medical and Health
2025-11-30 | Treatment of Severe Unconjugated Hyperbilirubinemia with Phenobarbitone in Two First-Degree Siblings with Crigler-Najjar Syndrome (CNS) Type 2: A Success Story
Background: Crigler–Najjar syndrome (CNS) type 2 is a rare autosomal recessive disorder of bilirubin conjugation caused by mutations in the UGT1A1 gene. It presents in infancy with unconjugated hyperbilirubinemia that does not respond to phototherapy but improves with phenobarbitone, which enhances residual enzyme activity. Although phenobarbitone remains the cornerstone of treatment, familial recurrence of CNS type 2 is rarely reported in pediatric literature. Case: We report two siblings born to consanguineous parents who presented with progressive jaundice during early infancy. The first child, a 2-month-old boy, had multiple hospitalisations for phototherapy without benefit. Laboratory evaluation revealed total bilirubin of 31 mg/dL with normal liver function and no evidence of hemolysis. Genetic testing confirmed a homozygous UGT1A1 (c.1456T>G; p.Tyr486Asp) mutation. He was treated with phenobarbitone (5–8 mg/kg/day) and calcium phosphate, achieving a bilirubin level <10 mg/dL within 4 weeks. Three years later, his younger sister developed similar unconjugated jaundice from day 4 of life and harboured the same mutation; she responded well to phenobarbitone alone. Both siblings remain well on long-term follow-up. Discussion: This case highlights the genetic basis and favorable response of CNS type 2 to phenobarbitone, which induces hepatic UGT1A1 expression. Familial clustering of CNS 2, though reported in few global studies, is seldom documented from India. Conclusion: Early genetic diagnosis, timely institution of phenobarbitone, and family counselling are critical for successful management of CNS type 2. These cases reaffirm the long-term safety and efficacy of phenobarbitone in familial presentations of this rare disorder.
2026-05-29 | Rewriting hepatic fate: emerging gene therapy strategies for liver disease
Several anatomical and physiological features make the liver particularly suitable for gene-based therapeutic strategies, including its extensive vascularization, fenestrated sinusoidal endothelium, and high metabolic capacity. In the past decade, liver-directed gene therapies have evolved from experimental concepts to clinical applications for various inherited and systemic disorders. Adeno-associated viral vectors, lentiviral systems, and lipid nanoparticles are currently the main platforms for delivering therapeutic genes and genome-editing tools to hepatocytes. Genome editing technologies such as CRISPR-Cas nucleases, base editors, and prime editors have enabled more precise modification of endogenous loci. Early clinical studies in disorders like hemophilia, transthyretin amyloidosis, ornithine transcarbamylase deficiency, and Crigler-Najjar syndrome show that partial correction of hepatic gene function can lead to meaningful clinical benefits. However, several challenges hinder broader clinical implementation, including immune responses to viral capsids and nanoparticle components, dose-dependent toxicity, limited packaging capacity of some vectors, and uncertainties about long-term safety and durability, especially in pediatric populations. Efficient and cell-type-specific delivery beyond hepatocytes remains a major challenge, particularly for diseases driven by non-parenchymal cells or malignant transformation. This article discusses recent advancements in delivery technologies and genome editing approaches for liver disease, as well as current translational barriers and emerging strategies aimed at enhancing specificity, durability, and safety. Collectively, these advances suggest that increasingly precise and programmable gene-based interventions may play a central role in future therapies for a broad spectrum of liver diseases.
2026-05-21 | Case Report: Retransplantation for Adult-Onset Bilirubin Encephalopathy After Auxiliary Partial Liver Transplant for Crigler-Najjar Syndrome Type 1 in Childhood.
Crigler-Najjar syndrome (CNS) type 1 is a genetic disorder that leads to severe unconjugated hyperbilirubinemia. Auxiliary partial orthotopic liver transplantation (APOLT) is preferred for metabolic liver diseases as a portion of the native liver is retained. Reported here are details of a 32-year-old male who developed bilirubin encephalopathy due to graft failure 27 years after APOLT performed at 5-year-old for CNS type 1. Initially, the bilirubin level was low, which then gradually increased to 7.3 mg/dL at age 12. At the age of 31, the bilirubin level began to rise rapidly and we submitted a request for deceased donor liver transplantation (DDLT) to the Committee for the Evaluation of Indications for DDLT in Japan. However, that was deemed as not indicated, because unconjugated bilirubin-dominant hyperbilirubinemia alone is generally not considered to cause encephalopathy in adults. Despite the high bilirubin level, the patient remained neurologically asymptomatic until occurrence of acute decompensation. At 32 years old, he was admitted on an emergency basis to our hospital with severe hyperbilirubinemia and neurological symptoms. After managing his general condition with intensive care, DDLT was finally performed, resulting in a drastic resolution of various symptoms. The findings in this case show that bilirubin-induced neurotoxicity in adults may be reversible and indicate that the current liver transplantation criteria used in Japan, which limit eligibility for CNS to pediatric patients, may have contributed to delayed transplantation. Re-evaluation of the transplant eligibility criteria is necessary to allow for a more inclusive approach that encompasses adult patients.
2026-01-09 | Engineering Liver-Specific Promoters: A Comprehensive Review of Design, Mechanisms, and Clinical Applications in Gene Therapy.
The liver is a primary metabolic hub and a pivotal target for gene therapy, owing to its capacity for protein secretion, role in metabolic homeostasis and immune tolerance. Liver-directed gene therapies are used to treat numerous inherited metabolic disorders and coagulation factor deficiencies including hemophilia (A and B), Crigler-Najjar syndrome, mucopolysaccharidoses, phenylketonuria, Fabry, Gaucher, Wilson and Pompe diseases. The efficacy and safety of liver-directed gene therapy rely on the use of strong tissue-specific promoters. To date, there are many different liver-specific promoters used in preclinical and clinical studies, including novel completely synthetic promoters. This review provides a comprehensive analysis of the design, engineering and application of liver-specific promoters. Furthermore, we discuss fundamental principles of gene expression regulation in the liver and the physiological and immunological characteristics that make it a suitable target organ for gene therapy delivery.
2025-12-01 | From Childhood Icterus to Adolescent Gallstones: Clinically Diagnosed Crigler-Najjar Syndrome Type II
From Childhood Icterus to Adolescent Gallstones: Clinically Diagnosed Crigler-Najjar Syndrome Type IIDanish Kumar GoswamiEmail: daniahgoswami34@gmail.com Institute/Affiliation: Department of Internal Medicine, Liaquat University of Medical and Health
2025-11-30 | Treatment of Severe Unconjugated Hyperbilirubinemia with Phenobarbitone in Two First-Degree Siblings with Crigler-Najjar Syndrome (CNS) Type 2: A Success Story
Background: Crigler–Najjar syndrome (CNS) type 2 is a rare autosomal recessive disorder of bilirubin conjugation caused by mutations in the UGT1A1 gene. It presents in infancy with unconjugated hyperbilirubinemia that does not respond to phototherapy but improves with phenobarbitone, which enhances residual enzyme activity. Although phenobarbitone remains the cornerstone of treatment, familial recurrence of CNS type 2 is rarely reported in pediatric literature. Case: We report two siblings born to consanguineous parents who presented with progressive jaundice during early infancy. The first child, a 2-month-old boy, had multiple hospitalisations for phototherapy without benefit. Laboratory evaluation revealed total bilirubin of 31 mg/dL with normal liver function and no evidence of hemolysis. Genetic testing confirmed a homozygous UGT1A1 (c.1456T>G; p.Tyr486Asp) mutation. He was treated with phenobarbitone (5–8 mg/kg/day) and calcium phosphate, achieving a bilirubin level <10 mg/dL within 4 weeks. Three years later, his younger sister developed similar unconjugated jaundice from day 4 of life and harboured the same mutation; she responded well to phenobarbitone alone. Both siblings remain well on long-term follow-up. Discussion: This case highlights the genetic basis and favorable response of CNS type 2 to phenobarbitone, which induces hepatic UGT1A1 expression. Familial clustering of CNS 2, though reported in few global studies, is seldom documented from India. Conclusion: Early genetic diagnosis, timely institution of phenobarbitone, and family counselling are critical for successful management of CNS type 2. These cases reaffirm the long-term safety and efficacy of phenobarbitone in familial presentations of this rare disorder.
Access all drug discovery papers and probability of success in trials forecasts:
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Drug Discovery Landscape
10 orphan drug designations for Crigler-Najjar syndrome.
10 orphan drug designations for Crigler-Najjar syndrome.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
rAAV8-hUGT1A1 | gene therapies | FDA | 2024-10-29 | — | Genethon |
Volrubigene ralaparvovec | gene therapies | EMA | 2016-11-18 | — | Audentes Therapeutics UK Limited |
modified mRNA encoding UGT1A1 protein, formulated in lipid nanoparticles | RNAs | FDA | 2016-07-05 | — | Moderna Therapeutics, Inc. |
Modified mRNA encoding the UGT1A1 protein | RNAs | EMA | 2016-06-27 | — | Moderna Biotech Spain S.L. |
non-replicating recombinant adeno-associated viral vector, serotype 8, expressing the 1A1 isoform of the bilirubin-uridine diphosphate glucuronosyltransferase gene | gene therapies | FDA | 2016-05-24 | — | Audentes Therapeutics, Inc. |
Adeno-associated viral vector serotype 8 containing the human UGT1A1 gene | gene therapies | EMA | 2014-10-15 | — | Généthon |
Volrubigene ralaparvovec | gene therapies | EMA | 2014-08-22 | — | Fondazione Telethon Ets |
heterologous human liver derived progenitor cells | cell therapies | FDA | 2012-03-09 | — | Promethera Biosciences |
Heterologous human adult liver derived stem cells | cell therapies | EMA | 2007-11-29 | — | Cellaion |
Flumecinol | small molecules | FDA | 1985-01-15 | — | Farmacon, Inc. |
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