Introduction of single base substitutions at homologous chromosomal sequences by adeno-associated virus vectors

Molecular Therapy : the Journal of the American Society of Gene Therapy
N InoueD W Russell

Abstract

Adeno-associated virus (AAV) vectors can modify homologous chromosomal sequences at high rates. This gene targeting transduction pathway is distinct from the integrating and episomal pathways used in gene addition approaches. In previous studies, AAV vectors were used to introduce small insertion and deletion mutations at homologous chromosomal loci. Here we show that AAV-mediated gene targeting can also be used to introduce all possible types of single base substitution mutations at the endogenous single-copy hypoxanthine phosphoribosyl transferase locus. Southern blot and sequence analysis showed that the point mutations were introduced with high fidelity. We also show that AAV vectors can repair chromosomal alkaline phosphatase genes containing point mutations. Our results suggest that AAV vectors can be used to introduce single base substitutions at high frequencies in normal human cells, including the correction of point mutations responsible for genetic diseases.

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Citations

Jun 1, 2005·Biotechnology Advances·David A Sorrell, Andreas F Kolb
Dec 3, 2002·Current Opinion in Biotechnology·Betsy T Kren, Clifford J Steer
Oct 25, 2003·Progress in Retinal and Eye Research·Enrico M Surace, Alberto Auricchio
Apr 2, 2011·Nature Protocols·Iram F KhanDavid W Russell
Nov 2, 2005·Nature Reviews. Microbiology·Ana Vasileva, Rolf Jessberger
Oct 24, 2007·Molecular Therapy : the Journal of the American Society of Gene Therapy·Joel R ChamberlainDavid W Russell
Apr 27, 2004·Cloning and Stem Cells·Roli K HirataDavid W Russell
Aug 6, 2008·Human Gene Therapy·David W Russell, Roli K Hirata
May 6, 2005·Human Gene Therapy·Grant TrobridgeDavid W Russell
Oct 11, 2005·Nucleic Acids Research·Ozlem TopalogluFred Bunz
Jul 16, 2004·Journal of Virology·Henry HamiltonErik Falck-Pedersen
May 2, 2003·Molecular and Cellular Biology·Daniel G MillerDavid W Russell
May 2, 2003·Molecular and Cellular Biology·Matthew H PorteusDavid Baltimore
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Feb 21, 2004·Science·Joel R ChamberlainDavid W Russell

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