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.
Highlights
Crigler-Najjar syndrome (CNs), severe unconjugated hyperbilirubinemia, results from the deficiency of UGT1A1, the enzyme that catalyzes the conjugation of unconjugated bilirubin (UCB) with UDP-glucuronic-acid [1]
To restrict the expression provided by an SV40 vector to the liver, a liver specific promoter was inserted between the SV40 early promoter and the luciferase gene generating the rSV-HLPLuc plasmid
In both hepatoma cell lines transduced with the rSV-hybrid liver specific promoter (HLP)-Luc vector, the luciferase intensity was significantly higher than in cells transduced with the rSV-Luc (Fig 2A and 2B)
Summary
Crigler-Najjar syndrome (CNs), severe unconjugated hyperbilirubinemia, results from the deficiency of UGT1A1, the enzyme that catalyzes the conjugation of unconjugated bilirubin (UCB) with UDP-glucuronic-acid [1]. If not treated effectively the severe form of CNs is lethal in childhood due to UCB accumulation to levels that cause irreversible brain damage [3]. Both lethality and brain damage can be prevented by intensive phototherapy, a cumbersome treatment that becomes less effective overtime [4, 5]. Most patients do need a liver transplant at some point in their life, a highly invasive treatment with several challenges, like the need for re-transplantation, toxicities and adverse effects associated with long-term immunosuppression [6]. Novel therapies are warranted, and recent clinical studies for other liver diseases, like hemophilia B show the potential of liver directed gene therapy [7]
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