Unrestricted hepatocyte transduction with adeno-associated virus serotype 8 vectors in mice

Hiroyuki Nakai, Sally Fuess, Theresa A. Storm, Shin Ichi Muramatsu, Yuko Nara, Mark A. Kay

Research output: Contribution to journalArticle

213 Citations (Scopus)

Abstract

Recombinant adeno-associated virus (rAAV) vectors can mediate long-term stable transduction in various target tissues. However, with rAAV serotype 2 (rAAV2) vectors, liver transduction is confined to only a small portion of hepatocytes even after administration of extremely high vector doses. In order to investigate whether rAAV vectors of other serotypes exhibit similar restricted liver transduction, we performed a dose-response study by injecting mice with β-galactosidase-expressing rAAV1 and rAAV8 vectors via the portal vein. The rAAV1 vector showed a blunted dose-response similar to that of rAAV2 at high doses, while the rAAV8 vector dose-response remained unchanged at any dose and ultimately could transduce all the hepatocytes at a dose of 7.2 × 1012 vector genomes/mouse without toxicity. This indicates that all hepatocytes have the ability to process incoming single-stranded vector genomes into duplex DNA. A single tail vein injection of the rAAV8 vector was as efficient as portal vein injection at any dose. In addition, intravascular administration of the rAAV8 vector at a high dose transduced all the skeletal muscles throughout the body, including the diaphragm, the entire cardiac muscle, and substantial numbers of cells in the pancreas, smooth muscles, and brain. Thus, rAAV8 is a robust vector for gene transfer to the liver and provides a promising research tool for delivering genes to various target organs. In addition, the rAAV8 vector may offer a potential therapeutic agent for various diseases affecting nonhepatic tissues, but great caution is required for vector spillover and tight control of tissue-specific gene expression.

Original languageEnglish (US)
Pages (from-to)214-224
Number of pages11
JournalJournal of Virology
Volume79
Issue number1
DOIs
StatePublished - Jan 2005
Externally publishedYes

Fingerprint

Dependovirus
hepatocytes
Hepatocytes
serotypes
Portal Vein
Liver
mice
dosage
Galactosidases
Genome
dose response
Injections
portal vein
Diaphragm
liver
Genes
Smooth Muscle
Tail
Pancreas
Veins

ASJC Scopus subject areas

  • Immunology

Cite this

Unrestricted hepatocyte transduction with adeno-associated virus serotype 8 vectors in mice. / Nakai, Hiroyuki; Fuess, Sally; Storm, Theresa A.; Muramatsu, Shin Ichi; Nara, Yuko; Kay, Mark A.

In: Journal of Virology, Vol. 79, No. 1, 01.2005, p. 214-224.

Research output: Contribution to journalArticle

Nakai, Hiroyuki ; Fuess, Sally ; Storm, Theresa A. ; Muramatsu, Shin Ichi ; Nara, Yuko ; Kay, Mark A. / Unrestricted hepatocyte transduction with adeno-associated virus serotype 8 vectors in mice. In: Journal of Virology. 2005 ; Vol. 79, No. 1. pp. 214-224.
@article{37201d8b2d8746b4938332801dc05468,
title = "Unrestricted hepatocyte transduction with adeno-associated virus serotype 8 vectors in mice",
abstract = "Recombinant adeno-associated virus (rAAV) vectors can mediate long-term stable transduction in various target tissues. However, with rAAV serotype 2 (rAAV2) vectors, liver transduction is confined to only a small portion of hepatocytes even after administration of extremely high vector doses. In order to investigate whether rAAV vectors of other serotypes exhibit similar restricted liver transduction, we performed a dose-response study by injecting mice with β-galactosidase-expressing rAAV1 and rAAV8 vectors via the portal vein. The rAAV1 vector showed a blunted dose-response similar to that of rAAV2 at high doses, while the rAAV8 vector dose-response remained unchanged at any dose and ultimately could transduce all the hepatocytes at a dose of 7.2 × 1012 vector genomes/mouse without toxicity. This indicates that all hepatocytes have the ability to process incoming single-stranded vector genomes into duplex DNA. A single tail vein injection of the rAAV8 vector was as efficient as portal vein injection at any dose. In addition, intravascular administration of the rAAV8 vector at a high dose transduced all the skeletal muscles throughout the body, including the diaphragm, the entire cardiac muscle, and substantial numbers of cells in the pancreas, smooth muscles, and brain. Thus, rAAV8 is a robust vector for gene transfer to the liver and provides a promising research tool for delivering genes to various target organs. In addition, the rAAV8 vector may offer a potential therapeutic agent for various diseases affecting nonhepatic tissues, but great caution is required for vector spillover and tight control of tissue-specific gene expression.",
author = "Hiroyuki Nakai and Sally Fuess and Storm, {Theresa A.} and Muramatsu, {Shin Ichi} and Yuko Nara and Kay, {Mark A.}",
year = "2005",
month = "1",
doi = "10.1128/JVI.79.1.214-224.2005",
language = "English (US)",
volume = "79",
pages = "214--224",
journal = "Journal of Virology",
issn = "0022-538X",
publisher = "American Society for Microbiology",
number = "1",

}

TY - JOUR

T1 - Unrestricted hepatocyte transduction with adeno-associated virus serotype 8 vectors in mice

AU - Nakai, Hiroyuki

AU - Fuess, Sally

AU - Storm, Theresa A.

AU - Muramatsu, Shin Ichi

AU - Nara, Yuko

AU - Kay, Mark A.

PY - 2005/1

Y1 - 2005/1

N2 - Recombinant adeno-associated virus (rAAV) vectors can mediate long-term stable transduction in various target tissues. However, with rAAV serotype 2 (rAAV2) vectors, liver transduction is confined to only a small portion of hepatocytes even after administration of extremely high vector doses. In order to investigate whether rAAV vectors of other serotypes exhibit similar restricted liver transduction, we performed a dose-response study by injecting mice with β-galactosidase-expressing rAAV1 and rAAV8 vectors via the portal vein. The rAAV1 vector showed a blunted dose-response similar to that of rAAV2 at high doses, while the rAAV8 vector dose-response remained unchanged at any dose and ultimately could transduce all the hepatocytes at a dose of 7.2 × 1012 vector genomes/mouse without toxicity. This indicates that all hepatocytes have the ability to process incoming single-stranded vector genomes into duplex DNA. A single tail vein injection of the rAAV8 vector was as efficient as portal vein injection at any dose. In addition, intravascular administration of the rAAV8 vector at a high dose transduced all the skeletal muscles throughout the body, including the diaphragm, the entire cardiac muscle, and substantial numbers of cells in the pancreas, smooth muscles, and brain. Thus, rAAV8 is a robust vector for gene transfer to the liver and provides a promising research tool for delivering genes to various target organs. In addition, the rAAV8 vector may offer a potential therapeutic agent for various diseases affecting nonhepatic tissues, but great caution is required for vector spillover and tight control of tissue-specific gene expression.

AB - Recombinant adeno-associated virus (rAAV) vectors can mediate long-term stable transduction in various target tissues. However, with rAAV serotype 2 (rAAV2) vectors, liver transduction is confined to only a small portion of hepatocytes even after administration of extremely high vector doses. In order to investigate whether rAAV vectors of other serotypes exhibit similar restricted liver transduction, we performed a dose-response study by injecting mice with β-galactosidase-expressing rAAV1 and rAAV8 vectors via the portal vein. The rAAV1 vector showed a blunted dose-response similar to that of rAAV2 at high doses, while the rAAV8 vector dose-response remained unchanged at any dose and ultimately could transduce all the hepatocytes at a dose of 7.2 × 1012 vector genomes/mouse without toxicity. This indicates that all hepatocytes have the ability to process incoming single-stranded vector genomes into duplex DNA. A single tail vein injection of the rAAV8 vector was as efficient as portal vein injection at any dose. In addition, intravascular administration of the rAAV8 vector at a high dose transduced all the skeletal muscles throughout the body, including the diaphragm, the entire cardiac muscle, and substantial numbers of cells in the pancreas, smooth muscles, and brain. Thus, rAAV8 is a robust vector for gene transfer to the liver and provides a promising research tool for delivering genes to various target organs. In addition, the rAAV8 vector may offer a potential therapeutic agent for various diseases affecting nonhepatic tissues, but great caution is required for vector spillover and tight control of tissue-specific gene expression.

UR - http://www.scopus.com/inward/record.url?scp=10644289281&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=10644289281&partnerID=8YFLogxK

U2 - 10.1128/JVI.79.1.214-224.2005

DO - 10.1128/JVI.79.1.214-224.2005

M3 - Article

C2 - 15596817

AN - SCOPUS:10644289281

VL - 79

SP - 214

EP - 224

JO - Journal of Virology

JF - Journal of Virology

SN - 0022-538X

IS - 1

ER -