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 - https://doi.org/10.1371/journal.pone.0250605
DO - https://doi.org/10.1371/journal.pone.0250605
M3 - Article
C2 - 33891666
SN - 1932-6203
VL - 16
JO - PLOS ONE
JF - PLOS ONE
IS - 4 April
M1 - e0250605
ER -