Gene Therapy for Inherited Hyperbilirubinemias

Roy‐Chowdhury, Namita; Kadakol, Ajit; Sappal, Baljit S.; Thummala, Narsing R.; Ghosh, Siddhartha Sankar; Lee, Sung W.; Roy‐Chowdhury, Jayanta

doi:10.1038/sj.jp.7210646

Cited by 14 publications

(10 citation statements)

References 20 publications

(12 reference statements)

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“…Hepatocyte transplantation and gene therapy methods are being explored as potential alternative therapeutic methods. [4][5][6] Gene therapy can be performed by site-directed mutagenesis, recombinant virus-based vectors or chimeric RNA/DNA oligonucleotide-based method, and has been successful mainly in animal researches. DNA/RNA chimera therapy seems very attractive as it targets to correct the mutation in a proportion of cells.…”

Section: Discussionmentioning

confidence: 99%

Severe hyperbilirubinaemia in a Chinese girl with type I Crigler–Najjar syndrome: First case ever reported in Mainland China

Nong

Xie

Chan

et al. 2005

J Paediatrics Child Health

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Jaundice is common in ethnic Chinese infants, but to our knowledge Crigler-Najjar syndrome (CN syndrome) type I has never been reported in China. A Chinese girl with severe jaundice was recently diagnosed to have CN syndrome type I by analyzing the bilirubin-uridinediphospho (UDP)-glucuronosyltransferase gene (UGT1A1). The patient was homozygous for a nonsense mutation that replaced glutamine (CAG, amino acid 239) with stop codon (TAG) at nucleotide number 715 (715C-->T) in exon 1. No mutation was found in exons 2-5. Her parents were heterozygous for the same mutant. The patient had an average bilirubin level of 300-500 mumol/L and a peak of 701 mumol/L. Daily phototherapy for 15 h was required to keep the bilirubin levels within 280-320 mumol/L. The unconjugated hyperbilirubinaemia apparently resulted from homozygous nonsense mutation of UGT1A1, which could completely abolish the UGT activity towards bilirubin (hepatic glucuronidation) and result in CN syndrome type I. Identification of the genetic defect is very useful for gene therapy, especially for DNA/RNA chimera therapy, and can be used as an antenatal screening test to identify the affected offsprings.

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Section: Discussionmentioning

confidence: 99%

Severe hyperbilirubinaemia in a Chinese girl with type I Crigler–Najjar syndrome: First case ever reported in Mainland China

Nong

Xie

Chan

et al. 2005

J Paediatrics Child Health

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“…Average age at transplantation was 9.1 ± 6.9 years (range, 1-23 years) [van der Veere et al 1996]. Hepatocyte transplantation has also been used in a Crigler-Najjar patient (Fox et al 1998], while gene therapy may also have promise for these patients in the future [Roy- Chowdhury 2001].…”

Section: Crigler-najjar Syndromes Types 1 Andmentioning

confidence: 99%

Bilirubin and the Genome: The Hereditary Basis of Unconjugated Neonatal Hyperbilirubinemia

Kaplan¹,

Hammerman²

2005

CPG

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Severe neonatal unconjugated hyperbilirubinemia, with the risk of bilirubin encephalopathy or kernicterus in severe, untreated cases, occurs when bilirubin production exceeds the body's ability to eliminate it. The causes of neonatal hyperbilirubinemia are multifactorial and comprise increased hemolysis on the one hand, and diminished bilirubin conjugation on the other. In recent years, many of these etiologies have been found to have a genetic origin. Sometimes hereditary factors act independently, but in other circumstances, single mutations which ordinarily do not produce disease in and of themselves, may result in severe hyperbilirubinemia as a result of interaction with other mutated genes. Of cardinal importance to this discussion is the concept of the human genome, whereby the thousands of genes of which it is comprised may interact one with the other, or with the environment, exacerbating the severity of jaundice in certain individuals, and protecting against hyperbilirubinemia in others. Genetic interactions have been demonstrated combining increased bilirubin production with diminished bilirubin conjugation, resulting in severe hyperbilirubinemia. Appreciation of the multiplicity of genetic interactions is of importance in our evaluation of the neonate with severe hyperbilirubinemia, in our attempts to prevent future cases of kernicterus, and in genetic counseling of families who have had an infant with severe neonatal hyperbilirubinemia. Gene therapy for the most severe of these inherited defects of bilirubin conjugation, Crigler-Najjar syndrome type 1, might become a reality in future years.

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“…Several gene-transfer methods have been extensively evaluated by using the Gunn rat (38). Among nonviral approaches, gene correction via chimeraplasty has been attempted (17), but its usefulness has been questioned (39).…”

Section: Discussionmentioning

confidence: 99%

Lifelong elimination of hyperbilirubinemia in the Gunn rat with a single injection of helper-dependent adenoviral vector

Toietta

Mane

Norona

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

126

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Crigler-Najjar syndrome is a recessively inherited disorder characterized by severe unconjugated hyperbilirubinemia caused by a deficiency of uridine diphospho-glucuronosyl transferase 1A1. Current therapy relies on phototherapy to prevent kernicterus, but liver transplantation presently is the only permanent cure. Gene therapy is a potential alternative, and recent work has shown that helper-dependent adenoviral (HD-Ad) vectors, devoid of all viral coding sequences, induce prolonged transgene expression and exhibit significantly less chronic toxicity than early-generation Ad vectors. We used a HD-Ad vector to achieve liver-restricted expression of human uridine diphospho-glucuronosyl transferase 1A1 in the Gunn rat, a model of the human disorder. Total plasma bilirubin levels were reduced from >5.0 mg͞dl to Ͻ Ͻ1.4 mg͞dl for >2 yr after a single i.v. administration of vector expressing the therapeutic transgene at a dose of 3 ؋ 10 12 viral particles per kg. HPLC analysis of bile from treated rats showed the presence of bilirubin glucuronides at normal WT levels >2 yr after one injection of vector, and i.v. injection of bilirubins III␣ and XIII␣ in the same animals revealed excess bilirubin-conjugating capacity. There was no significant elevation of liver enzymes (alanine aminotransferase) and only transient, moderate thrombocytopenia after injection of the vector. A clinically significant reduction in serum bilirubin was observed with a dose as low as 6 ؋ 10 11 viral particles per kg. We conclude that complete, long-term correction of hyperbilirubinemia in the Gunn rat model of Crigler-Najjar syndrome can be achieved with one injection of HD-Ad vector and negligible chronic toxicity.adenovirus ͉ bilirubin ͉ gene therapy

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Gene Therapy for Inherited Hyperbilirubinemias

Cited by 14 publications

References 20 publications

Severe hyperbilirubinaemia in a Chinese girl with type I Crigler–Najjar syndrome: First case ever reported in Mainland China

Severe hyperbilirubinaemia in a Chinese girl with type I Crigler–Najjar syndrome: First case ever reported in Mainland China

Bilirubin and the Genome: The Hereditary Basis of Unconjugated Neonatal Hyperbilirubinemia

Lifelong elimination of hyperbilirubinemia in the Gunn rat with a single injection of helper-dependent adenoviral vector

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