Rescue of bilirubin‐induced neonatal lethality in a mouse model of Crigler‐Najjar syndrome type I by AAV9‐mediated gene transfer

Bortolussi, Giulia; Zentilin, Lorena; Baj, Gabriele; Giraudi, Pablo J.; Bellarosa, Cristina; Giacca, Mauro; Tiribelli, Claudio; Muro, Andrés F.

doi:10.1096/fj.11-195461

Cited by 73 publications

(168 citation statements)

References 37 publications

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“…Ugt1 mutant mice have been described previously (Bortolussi et al, 2012). WT littermates were used as a control.…”

Section: Animalsmentioning

confidence: 99%

“…In the latter case, involving AAV vectors, efficacy was more evident (approximately 50% reduction compared with untreated controls) and long lasting (Bortolussi et al, 2012;Pastore et al, 2012). We have recently shown that neonatal gene transfer of AAV9-CMV-hUGT1A1 to the skeletal muscle can rescue bilirubin-induced lethality in a lethal murine model of CNSI we developed (Bortolussi et al, 2012).…”

Section: Introductionmentioning

confidence: 98%

“…In the former case, a rapid drop of the therapeutic effect was observed, which was associated with the loss of UGT1A1 protein expression after a couple of weeks postinjection of the plasmid DNA (Danko et al, 2004;Jia and Danko, 2005). In the latter case, involving AAV vectors, efficacy was more evident (approximately 50% reduction compared with untreated controls) and long lasting (Bortolussi et al, 2012;Pastore et al, 2012). We have recently shown that neonatal gene transfer of AAV9-CMV-hUGT1A1 to the skeletal muscle can rescue bilirubin-induced lethality in a lethal murine model of CNSI we developed (Bortolussi et al, 2012).…”

Section: Introductionmentioning

confidence: 98%

“…In both AAV approaches targeting skeletal muscle in rats and mice, UGT1A1 expression levels in this tissue were comparable to those of wild type (WT) liver (Bortolussi et al, 2012;Pastore et al, 2012). However, they were accompanied by a less than ideal reduction of total bilirubin (TB) values, suggesting that other factors are necessary to attain therapeutic success.…”

Section: Introductionmentioning

confidence: 99%

“…Because of these favorable characteristics, it is not surprising that several of the clinical trials for liver metabolic diseases performed to date have entailed intramuscular gene delivery (Mingozzi and High, 2011). In particular, various gene therapy approaches have been performed in the animal models of CNSI by targeting skeletal muscle, including injections of naked plasmid DNA and the use of AAV vectors (Danko et al, 2004;Jia and Danko, 2005;Bortolussi et al, 2012;Pastore et al, 2012). In the former case, a rapid drop of the therapeutic effect was observed, which was associated with the loss of UGT1A1 protein expression after a couple of weeks postinjection of the plasmid DNA (Danko et al, 2004;Jia and Danko, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Life-Long Correction of Hyperbilirubinemia with a Neonatal Liver-Specific AAV-Mediated Gene Transfer in a Lethal Mouse Model of Crigler–Najjar Syndrome

Bortolussi

Zentillin²,

Vaníková³

et al. 2014

Human Gene Therapy

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104

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Null mutations in the UGT1A1 gene result in Crigler-Najjar syndrome type I (CNSI), characterized by severe hyperbilirubinemia and constant risk of developing neurological damage. Phototherapy treatment lowers plasma bilirubin levels, but its efficacy is limited and liver transplantation is required. To find alternative therapies, we applied AAV liver-specific gene therapy to a lethal mouse model of CNSI. We demonstrated that a single neonatal hUGT1A1 gene transfer was successful and the therapeutic effect lasted up to 17 months postinjection. The therapeutic effect was mediated by the presence of transcriptionally active double-stranded episomes. We also compared the efficacy of two different gene therapy approaches: liver versus skeletal muscle transgene expression. We observed that 5-8% of normal liver expression and activity levels were sufficient to significantly reduce bilirubin levels and maintain lifelong low plasma bilirubin concentration (3.1 -1.5 mg/dl). In contrast, skeletal muscle was not able to efficiently lower bilirubin (6.4 -2.0 mg/dl), despite 20-30% of hUgt1a1 expression levels, compared with normal liver. We propose that this remarkable difference in gene therapy efficacy could be related to the absence of the Mrp2 and Mrp3 transporters of conjugated bilirubin in muscle. Taken together, our data support the concept that liver is the best organ for efficient and long-term CNSI gene therapy, and suggest that the use of extra-hepatic tissues should be coupled to the presence of bilirubin transporters.

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“…Ugt1 mutant mice have been described previously (Bortolussi et al, 2012). WT littermates were used as a control.…”

Section: Animalsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Life-Long Correction of Hyperbilirubinemia with a Neonatal Liver-Specific AAV-Mediated Gene Transfer in a Lethal Mouse Model of Crigler–Najjar Syndrome

Bortolussi

Zentillin²,

Vaníková³

et al. 2014

Human Gene Therapy

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104

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Congenital Deafness and Recent Advances Towards Restoring Hearing Loss

Renauld

Basch

2021

Current Protocols

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Congenital hearing loss is the most common birth defect, estimated to affect 2‐3 in every 1000 births. Currently there is no cure for hearing loss. Treatment options are limited to hearing aids for mild and moderate cases, and cochlear implants for severe and profound hearing loss. Here we provide a literature overview of the environmental and genetic causes of congenital hearing loss, common animal models and methods used for hearing research, as well as recent advances towards developing therapies to treat congenital deafness. © 2021 The Authors.

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Severe neonatal hyperbilirubinemia in Crigler‐Najjar syndrome model mice can be reversed with zinc protoporphyrin

Fujiwara

Mitsugi

Uemura

et al. 2017

Hepatology Communications

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Neurotoxic bilirubin is solely conjugated by UDP-glucuronosyltransferase (UGT) 1A1. Due to an inadequate function of UGT1A1, human neonates develop mild to severe physiological hyperbilirubinemia. Accumulation of bilirubin in the brain leads to the onset of irreversible brain damage called kernicterus. Breastfeeding is one of the most significant factors that increase the risk of developing kernicterus in infants. Why does the most natural way of feeding increase the risk of brain damage or even death? This question leads to the hypothesis that breast milk-induced neonatal hyperbilirubinemia might bring certain benefits to the body. One of the barriers to answering the above question is the lack of animal models that display mild to severe neonatal hyperbilirubinemia. A mouse model that develops neonatal hyperbilirubinemia was previously developed by a knockout of the Ugt1 locus. Deletion of Ugt1a1 results in neonatal lethality from bilirubin neurotoxicity. Bilirubin is the end product of heme catabolism in which heme oxygenase-I is largely involved. When zinc protoporphyrin, an inhibitor of heme oxygenase I, was administered to newborn Ugt1−/− mice, serum bilirubin levels dropped dramatically, rescuing the mice from bilirubin-induced neonatal lethality. Zinc protoporphyrin-treated Ugt1−/− mice developed normally as adults capable of reproducing, but their newborns showed even more severe hyperbilirubinemia. Microarray analysis of the hyperbilirubinemic livers indicated that a number of genes associated with nucleotide, transport, and immune response were significantly down-regulated in a serum bilirubin level-dependent manner. Conclusion: Our study provides an opportunity to advance the development of effective therapeutics to effectively and rapidly prevent bilirubin-induced toxicity. Neonatal hyperbilirubinemia has various impacts on the body that could be driven by the antioxidant property of bilirubin.

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Rescue of bilirubin‐induced neonatal lethality in a mouse model of Crigler‐Najjar syndrome type I by AAV9‐mediated gene transfer

Cited by 73 publications

References 37 publications

Life-Long Correction of Hyperbilirubinemia with a Neonatal Liver-Specific AAV-Mediated Gene Transfer in a Lethal Mouse Model of Crigler–Najjar Syndrome

Life-Long Correction of Hyperbilirubinemia with a Neonatal Liver-Specific AAV-Mediated Gene Transfer in a Lethal Mouse Model of Crigler–Najjar Syndrome

Congenital Deafness and Recent Advances Towards Restoring Hearing Loss

Severe neonatal hyperbilirubinemia in Crigler‐Najjar syndrome model mice can be reversed with zinc protoporphyrin

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