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Repeated AAV-mediated gene transfer by serotype switching enables long-lasting therapeutic levels of hUgt1a1 enzyme in a mouse model of Crigler-Najjar Syndrome Type i

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Repeated AAV-mediated gene transfer by serotype switching enables long-lasting therapeutic levels of hUgt1a1 enzyme in a mouse model of Crigler-Najjar Syndrome Type i. / Bočkor, L.; Bortolussi, G.; Iaconcig, A.; Chiaruttini, G.; Tiribelli, C.; Giacca, M.; Benvenuti, F.; Zentilin, L.; Muro, A. F.

In: Gene Therapy, Vol. 24, No. 10, 01.10.2017, p. 649-660.

Research output: Contribution to journalArticle

Harvard

Bočkor, L, Bortolussi, G, Iaconcig, A, Chiaruttini, G, Tiribelli, C, Giacca, M, Benvenuti, F, Zentilin, L & Muro, AF 2017, 'Repeated AAV-mediated gene transfer by serotype switching enables long-lasting therapeutic levels of hUgt1a1 enzyme in a mouse model of Crigler-Najjar Syndrome Type i', Gene Therapy, vol. 24, no. 10, pp. 649-660. https://doi.org/10.1038/gt.2017.75

APA

Bočkor, L., Bortolussi, G., Iaconcig, A., Chiaruttini, G., Tiribelli, C., Giacca, M., Benvenuti, F., Zentilin, L., & Muro, A. F. (2017). Repeated AAV-mediated gene transfer by serotype switching enables long-lasting therapeutic levels of hUgt1a1 enzyme in a mouse model of Crigler-Najjar Syndrome Type i. Gene Therapy, 24(10), 649-660. https://doi.org/10.1038/gt.2017.75

Vancouver

Bočkor L, Bortolussi G, Iaconcig A, Chiaruttini G, Tiribelli C, Giacca M et al. Repeated AAV-mediated gene transfer by serotype switching enables long-lasting therapeutic levels of hUgt1a1 enzyme in a mouse model of Crigler-Najjar Syndrome Type i. Gene Therapy. 2017 Oct 1;24(10):649-660. https://doi.org/10.1038/gt.2017.75

Author

Bočkor, L. ; Bortolussi, G. ; Iaconcig, A. ; Chiaruttini, G. ; Tiribelli, C. ; Giacca, M. ; Benvenuti, F. ; Zentilin, L. ; Muro, A. F. / Repeated AAV-mediated gene transfer by serotype switching enables long-lasting therapeutic levels of hUgt1a1 enzyme in a mouse model of Crigler-Najjar Syndrome Type i. In: Gene Therapy. 2017 ; Vol. 24, No. 10. pp. 649-660.

Bibtex Download

@article{59d65250b97e4c1bb2ea83482536e33a,
title = "Repeated AAV-mediated gene transfer by serotype switching enables long-lasting therapeutic levels of hUgt1a1 enzyme in a mouse model of Crigler-Najjar Syndrome Type i",
abstract = "Adeno-Associated virus (AAV)-mediated gene therapy is a promising strategy to treat liver-based monogenic diseases. However, two major obstacles limit its success: first, vector dilution in actively dividing cells, such as hepatocytes in neonates/children, due to the non-integrating nature of the vector; second, development of an immune response against the transgene and/or viral vector. Crigler-Najjar Syndrome Type I is a rare monogenic disease with neonatal onset, caused by mutations in the liver-specific UGT1 gene, with toxic accumulation of unconjugated bilirubin in plasma, tissues and brain. To establish an effective and long lasting cure, we applied AAV-mediated liver gene therapy to a relevant mouse model of the disease. Repeated gene transfer to adults by AAV-serotype switching, upon neonatal administration, resulted in lifelong correction of total bilirubin (TB) levels in both genders. In contrast, vector loss over time was observed after a single neonatal administration. Adult administration resulted in lifelong TB levels correction in male, but not female Ugt1-/-mice. Our findings demonstrate that neonatal AAV-mediated gene transfer to the liver supports a second transfer of the therapeutic vector, by preventing the induction of an immune response and supporting the possibility to improve AAV-Therapeutic efficacy by repeated administration.",
author = "L. Bo{\v c}kor and G. Bortolussi and A. Iaconcig and G. Chiaruttini and C. Tiribelli and M. Giacca and F. Benvenuti and L. Zentilin and Muro, {A. F.}",
year = "2017",
month = oct,
day = "1",
doi = "10.1038/gt.2017.75",
language = "English",
volume = "24",
pages = "649--660",
journal = "Gene Therapy",
issn = "0969-7128",
publisher = "Nature Publishing Group",
number = "10",

}

RIS (suitable for import to EndNote) Download

TY - JOUR

T1 - Repeated AAV-mediated gene transfer by serotype switching enables long-lasting therapeutic levels of hUgt1a1 enzyme in a mouse model of Crigler-Najjar Syndrome Type i

AU - Bočkor, L.

AU - Bortolussi, G.

AU - Iaconcig, A.

AU - Chiaruttini, G.

AU - Tiribelli, C.

AU - Giacca, M.

AU - Benvenuti, F.

AU - Zentilin, L.

AU - Muro, A. F.

PY - 2017/10/1

Y1 - 2017/10/1

N2 - Adeno-Associated virus (AAV)-mediated gene therapy is a promising strategy to treat liver-based monogenic diseases. However, two major obstacles limit its success: first, vector dilution in actively dividing cells, such as hepatocytes in neonates/children, due to the non-integrating nature of the vector; second, development of an immune response against the transgene and/or viral vector. Crigler-Najjar Syndrome Type I is a rare monogenic disease with neonatal onset, caused by mutations in the liver-specific UGT1 gene, with toxic accumulation of unconjugated bilirubin in plasma, tissues and brain. To establish an effective and long lasting cure, we applied AAV-mediated liver gene therapy to a relevant mouse model of the disease. Repeated gene transfer to adults by AAV-serotype switching, upon neonatal administration, resulted in lifelong correction of total bilirubin (TB) levels in both genders. In contrast, vector loss over time was observed after a single neonatal administration. Adult administration resulted in lifelong TB levels correction in male, but not female Ugt1-/-mice. Our findings demonstrate that neonatal AAV-mediated gene transfer to the liver supports a second transfer of the therapeutic vector, by preventing the induction of an immune response and supporting the possibility to improve AAV-Therapeutic efficacy by repeated administration.

AB - Adeno-Associated virus (AAV)-mediated gene therapy is a promising strategy to treat liver-based monogenic diseases. However, two major obstacles limit its success: first, vector dilution in actively dividing cells, such as hepatocytes in neonates/children, due to the non-integrating nature of the vector; second, development of an immune response against the transgene and/or viral vector. Crigler-Najjar Syndrome Type I is a rare monogenic disease with neonatal onset, caused by mutations in the liver-specific UGT1 gene, with toxic accumulation of unconjugated bilirubin in plasma, tissues and brain. To establish an effective and long lasting cure, we applied AAV-mediated liver gene therapy to a relevant mouse model of the disease. Repeated gene transfer to adults by AAV-serotype switching, upon neonatal administration, resulted in lifelong correction of total bilirubin (TB) levels in both genders. In contrast, vector loss over time was observed after a single neonatal administration. Adult administration resulted in lifelong TB levels correction in male, but not female Ugt1-/-mice. Our findings demonstrate that neonatal AAV-mediated gene transfer to the liver supports a second transfer of the therapeutic vector, by preventing the induction of an immune response and supporting the possibility to improve AAV-Therapeutic efficacy by repeated administration.

UR - http://www.scopus.com/inward/record.url?scp=85032457670&partnerID=8YFLogxK

U2 - 10.1038/gt.2017.75

DO - 10.1038/gt.2017.75

M3 - Article

C2 - 28805798

AN - SCOPUS:85032457670

VL - 24

SP - 649

EP - 660

JO - Gene Therapy

JF - Gene Therapy

SN - 0969-7128

IS - 10

ER -

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