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

Nickerson, Helen D.; Colledge, William H

doi:10.1038/sj.gt.3302311

Cited by 13 publications

(8 citation statements)

References 38 publications

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“…Thus one, or several DNA maintenance pathways, or DNA damage checkpoints, may have to be altered before ssODN are able to introduce a mutation in the template genome at any measurable rates. A hypothesized necessity for a lack of one or several repair pathways or damage checkpoint pathways could offer an explanation to why -using current technology -targeted sequence alteration with ssODN works relatively well in some cell lines, like CHO and HEK 293 cells, while there are conflicting reports whether the technique works in untransformed wt cells or animal models [13,[40][41][42].…”

Section: Discussionmentioning

confidence: 95%

Genomic sequence correction by single‐stranded DNA oligonucleotides: role of DNA synthesis and chemical modifications of the oligonucleotide ends

Olsen

Randøl

Luna

et al. 2005

The Journal of Gene Medicine

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Section: Discussionmentioning

confidence: 95%

Genomic sequence correction by single‐stranded DNA oligonucleotides: role of DNA synthesis and chemical modifications of the oligonucleotide ends

Olsen

Randøl

Luna

et al. 2005

The Journal of Gene Medicine

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“…In doing so, these studies provided the essential validation and framework for all AAV‐mediated gene repair studies in vivo . 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. One report has shown limited efficacy in vivo using a neonatal mouse model of the disease mucopolysaccharidosis type VII 15.…”

Section: Discussionmentioning

confidence: 99%

Adeno-associated virus gene repair corrects a mouse model of hereditary tyrosinemia in vivo

et al. 2009

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Adeno-associated virus (AAV) vectors are ideal for performing gene repair due to their ability to target multiple different genomic loci, low immunogenicity, capability to achieve targeted and stable expression through integration, and low mutagenic and oncogenic potential. However, many handicaps to gene repair therapy remain. Most notable is the low frequency of correction in vivo. To date, this frequency is too low to be of therapeutic value for any disease. To address this, a point-mutation– based mouse model of the metabolic disease hereditary tyrosinemia type I was used to test whether targeted AAV integration by homologous recombination could achieve high-level stable gene repair in vivo. Both neonatal and adult mice were treated with AAV serotypes 2 and 8 carrying a wild-type genomic sequence for repairing the mutated Fah (fumarylacetoacetate hydrolase) gene. Hepatic gene repair was quantified by immunohistochemistry and supported with reverse transcription polymerase chain reaction and serology for functional correction parameters. Successful gene repair was observed with both serotypes but was more efficient with AAV8. Correction frequencies of up to 10−3 were achieved and highly reproducible within typical dose ranges. In this model, repaired hepatocytes have a selective growth advantage and are thus able to proliferate to efficiently repopulate mutant livers and cure the underlying metabolic disease. Conclusion AAV-mediated gene repair is feasible in vivo and can functionally correct an appropriate selection-based metabolic liver disease in both adults and neonates.

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“…However, not all animal models generate high levels of correction. Nickerson et al 33 have established a LacZ mouse model for testing gene repair activity and initial results were quite disappointing as no correction was detected using a variety of vectors. As portrayed by these authors, the delivery of the oligonucleotide in sufficient numbers to a particular tissue may be a continual problem for this approach.…”

Section: Single-stranded Dna Catalyzes Gene Repair Most Effectivelymentioning

confidence: 99%

Gene therapy progress and prospects: targeted gene repair

et al. 2005

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The capacity to correct a mutant gene within the context of the chromosome holds great promise as a therapy for inherited disorders but fulfilling this promise has proven to be challenging. However, steady progress is being made and the development of gene repair as a viable and robust approach is underway. Here, we present some of the recent advances that are helping to shape our thinking about the feasibility and the limitations of this technique. For the most part, these advances center on understanding the regulation of the reaction and validating its application in animal models. Gene Therapy (2005) 12, 639-646.

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

Cited by 13 publications

References 38 publications

Genomic sequence correction by single‐stranded DNA oligonucleotides: role of DNA synthesis and chemical modifications of the oligonucleotide ends

Genomic sequence correction by single‐stranded DNA oligonucleotides: role of DNA synthesis and chemical modifications of the oligonucleotide ends

Adeno-associated virus gene repair corrects a mouse model of hereditary tyrosinemia in vivo

Gene therapy progress and prospects: targeted gene repair

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