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Low efficacy of recombinant SV40 in Ugt1a1-/- mice with severe inherited hyperbilirubinemia. / Shi, Xiaoxia; Bortolussi, Giulia; ten Bloemendaal, Lysbeth; Duijst, Suzanne; Muro, Andrés F.; Bosma, Piter J.

In: PLoS ONE, Vol. 16, No. 4 April, e0250605, 01.04.2021.

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@article{73eff083026d4d0f86ab9924c9d3cf78,
title = "Low efficacy of recombinant SV40 in Ugt1a1-/- mice with severe inherited hyperbilirubinemia",
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.",
author = "Xiaoxia Shi and Giulia Bortolussi and {ten Bloemendaal}, Lysbeth and Suzanne Duijst and Muro, {Andr{\'e}s F.} and Bosma, {Piter J.}",
note = "Publisher Copyright: {\textcopyright} 2021 Shi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",
year = "2021",
month = apr,
day = "1",
doi = "10.1371/journal.pone.0250605",
language = "English",
volume = "16",
journal = "PLoS ONE",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "4 April",

}

RIS

TY - JOUR

T1 - Low efficacy of recombinant SV40 in Ugt1a1-/- mice with severe inherited hyperbilirubinemia

AU - Shi, Xiaoxia

AU - Bortolussi, Giulia

AU - ten Bloemendaal, Lysbeth

AU - Duijst, Suzanne

AU - Muro, Andrés F.

AU - Bosma, Piter J.

N1 - Publisher Copyright: © 2021 Shi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PY - 2021/4/1

Y1 - 2021/4/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85104591970&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0250605

DO - 10.1371/journal.pone.0250605

M3 - Article

C2 - 33891666

VL - 16

JO - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

IS - 4 April

M1 - e0250605

ER -

ID: 18021076