Evaluation of Transduction Properties of an Adenovirus Vector in Neonatal Mice

Shunsuke Iizuka,Kazuo Ohashi,Shin-Ichiro Nakamura,Fuminori Sakurai,Masashi Tachibana,Kahori Shimizu,Hiroyuki Mizuguchi

doi:10.1155/2015/685374

Shunsuke Iizuka, Kazuo Ohashi + Show 5 more

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https://doi.org/10.1155/2015/685374

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Abstract

In gene therapy for congenital disorders, treatments during neonate and infant stages are promising. Replication-incompetent adenovirus (Ad) vectors have been used in gene therapy studies of genetic disorders; however, the transduction properties of Ad vectors in neonates and infants have not been fully examined. Accordingly, this study examined the properties of Ad vector-mediated transduction in neonatal mice. A first-generation Ad vector containing a cytomegalovirus (CMV) promoter-driven luciferase expression cassette was administered to neonatal mice on the second day of life via retro-orbital sinus. The highest Ad vector genome copy numbers and transgene expression were found in the neonatal liver. The neonatal heart exhibited the second highest levels of transgene expression among the organs examined. There was an approximately 1500-fold difference in the transgene expression levels between the adult liver and heart, while the neonatal liver exhibited only an approximately 30-fold higher level of transgene expression than the neonatal heart. A liver-specific promoter for firefly luciferase expression conferred a more than 100-fold higher luciferase expression in the liver relative to the other organs. No apparent hepatotoxicity was observed in neonatal mice following Ad vector administration. These findings should provide valuable information for gene therapy using Ad vectors in neonates and infants.

Highlights

The mechanisms of several congenital diseases have been gradually revealed; efficient treatment protocols have not been established for most congenital diseases, including X-linked severe combined immune deficiency (X-SCID), hemophilia, and lysosomal storage disorder.The existing supportive treatments, such as enzyme replacement treatment, often do not achieve sufficient therapeutic effects
The result showed that the serum levels of creatine kinase (CK), a cardiac toxicity marker, were not significantly elevated in the Ad vector-injected group compared with the PBS-injected group, suggesting that systemic administration of an Ad vector to neonatal mice did not induce apparent hepatic or cardiac toxicity (Figure 4(d))
Ad vectors have been used in numerous preclinical studies employing mouse models of congenital disease [20,21,22,23], the properties of Ad vector transduction in neonates have not been fully examined

Summary

Introduction

The mechanisms of several congenital diseases have been gradually revealed; efficient treatment protocols have not been established for most congenital diseases, including X-linked severe combined immune deficiency (X-SCID), hemophilia, and lysosomal storage disorder. Ad vectors have been used in gene therapy clinical trials of adult patients with various diseases, including several types of cancers and cardiac diseases, and promising results have been reported [9, 10]. These various advantageous properties of Ad vectors led us to consider that they might be suitable for gene therapy in neonates and infants; the transduction properties of Ad vectors in neonates and infants have not been fully examined. The results should be highly informative for gene therapy in neonates and infants as well as basic studies using neonatal mice

Materials and Methods

Results

Background level

Discussion