A LacZ-based transgenic mouse for detection of somatic gene repair events in vivo

Nickerson, H D; Colledge, W H

doi:10.1038/sj.gt.3302311

Cited by 17CRISPR and Genetic EngineeringDNA Repair MechanismsAnimal Genetics and Reproduction

A LacZ-based transgenic mouse for detection of somatic gene repair events in vivo

Nickerson, H D, Colledge, W H·2004·Gene Therapy

DOI 10.1038/sj.gt.3302311

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Abstract

Somatic gene repair of disease-causing chromosomal mutations is a novel approach for gene therapy. This method would ensure that the corrected gene is regulated by its endogenous promoter and expressed at physiological levels in the appropriate cell types. A reporter mouse, Gtrosa26(tm1Col), was generated by targeting a mutated LacZ gene to the Rosa26 locus in mouse embryonic stem (ES) cells. The LacZ gene contains a G to A point mutation, resulting in a Glu to Lys amino-acid substitution at position 461, which abrogates enzymatic activity. The gene is expressed in ES cells, primary embryonic fibroblasts, and in all tissues examined in the adult mouse, including the lung, liver, kidney, spleen, heart, brain and smooth muscle. This transgenic mouse will allow testing of gene repair strategies in vivo and identification of which cell types can be successfully targeted by chromosomal gene repair. Although low levels of gene repair were achieved in the ES cells used to generate the Gtrosa26(tm1Col) mouse, preliminary attempts at gene repair in vivo were unsuccessful, thus highlighting the difficulties that will have to be overcome to get this approach to work.

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Few publications exist demonstrating repair in vivo, and they are hindered by targeting clinically irrelevant marker mutations in exogenously provided transgenes like GFP or LacZ.
“Few publications exist demonstrating repair in vivo,39,40 and they are hindered by the fact that they target clinically irrelevant marker mutations in exogenously provided transgenes like green fluorescent protein (GFP) or LacZ.”
From Adeno‐associated virus gene repair corrects a mouse model of hereditary tyrosinemia in vivo†‡ (2010) · cites this paper as [40]

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A comparison of gene repair strategies in cell culture using a lacZ reporter system
Nickerson, H. D., & Colledge, W. H. (2003) · Gene Therapy · doi:10.1038/sj.gt.3302049 · Cited by 41 · see citing works
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Authors: Nickerson, H. D., & Colledge, W. H.
Affiliations: University of Cambridge (GB)
ORCID: Nickerson, H D
Colledge, W H
Venue: Gene Therapy
Publisher: Springer Science and Business Media LLC
Published: 2004-07-01
Volume: 11
Issue: 17
Pages: 1351-1357
ISSN: 0969-7128 (ISSN-L)
1476-5462
DOI: 10.1038/sj.gt.3302311
OpenAlex: W1969405745
Cited by: 17
References: 36
Citations by year: 2025: 1 · 2024: 1 · 2022: 2 · 2021: 1 · 2015: 1 · 2012: 2
FWCI: 0.71
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Gene Therapy (publishedVersion)
PubMed (publishedVersion)
Funders: Medical Research Council
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Animal Genetics and Reproduction
Keywords: chromosomal mutations, Rosa26 locus, point mutations, transgenic mice, embryonic stem cells, tissue-specific gene expression
MeSH terms: Animals, beta-Galactosidase, Cells, Cultured, Lac Operon, Liver, Mice, Transgenic, Stem Cells, Transfection, Blotting, Western, Genetic Therapy, Gene Expression, Electroporation, Gene Targeting, Models, Animal, Mice

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A LacZ-based transgenic mouse for detection of somatic gene repair events in vivo

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