In Vivo Drug‐Selectable Genes: A New Concept in Gene Therapy

Licht, Thomas; Herrmann, F; Gottesman, M M; Pastan, Ira

doi:10.1002/stem.150104

Cited by 35 publications

(13 citation statements)

References 75 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, there are in vivo-selectable genes which could replace the hygromycin as dominant marker drug. 36 The development of episomal gene delivery vectors that can deliver sustained gene expression, without potentially harmful integration, would be advantageous in treating patients with various and common genetic deficiencies via gene therapy.…”

Section: Differential Long-term Functionality Of Various Transactivatmentioning

confidence: 99%

An enhanced EBNA1 variant with reduced IR3 domain for long-term episomal maintenance and transgene expression of oriP-based plasmids in human cells

Wendelburg

Vos

1998

Gene Ther

View full text Add to dashboard Cite

The latent replication of oriP-based plasmids in human IR3-deleted, form, as well as a new EBNA1 isoform cloned cells depends on the viral oriP-binding transactivator from Raji. The results of a 6-month study indicate that the EBNA1. In this report, the effect of the internal repeat 3 isoforms of EBNA1 differ with respect to their efficiency of (IR3 or GlyAla repeat) domain of EBNA1 on long-term plasmid maintenance. While the EBNA-1 Raji encoding maintenance and transgene expression of OriP-based plasmid was the most stable, the oriP-based vector plasmids was examined in dividing human cells. To assess expressing the truncated EBNA1 (IR3del) gene was lost at the potential contribution of different isoforms of EBNA1 a much higher rate than those transducing full size specifically, the long-term stability of oriP-based plasmids EBNA1s. In parallel, long-term reporter gene expression in was determined after stable transfection of various CMVvarious human B cell lines was shown to persist at the driven EBNA1 genes in EBV-negative human B cells. Epihighest level with the oriP-based Raji EBNA-1 construct. some copy number was quantified using a novel sensitive These results show that the GlyAla domain can positively assay based on human mitochondrial DNA as an internal influence long-term plasmid stability and episomal transextrachromosomal control. Using this assay, the standard gene expression. B95.8-derived EBNA1 was compared with its truncated,

show abstract

Section: Differential Long-term Functionality Of Various Transactivatmentioning

confidence: 99%

An enhanced EBNA1 variant with reduced IR3 domain for long-term episomal maintenance and transgene expression of oriP-based plasmids in human cells

Wendelburg

Vos

1998

Gene Ther

View full text Add to dashboard Cite

show abstract

“…Although Neo R has been employed in hematopoietic cells in some studies, 23 this selection system cannot be applied in vivo due to the toxicity of neomycin. 24 Also, expression of such a bacterial gene in humans has the potential to act as a neo-antigen leading to an undesirable immunologic response. Antibodies against neomycin phosphotransferase have been found in the canine model of mucopolysaccharidosis I.…”

Section: Introductionmentioning

confidence: 99%

Retroviral vector design studies toward hematopoietic stem cell gene therapy for mucopolysaccharidosis type I

et al. 2000

View full text Add to dashboard Cite

“…A very interesting approach to compensate for this limitation would be dominant selection ex vivo or in vivo of the gene -modified cells. 5 Several drug -resistance genes related to cancer have been investigated for their potential for protection of normal cells against cancer chemotherapy. The protection of normal cells from drug toxicity is an interesting approach to improve the effectiveness of cancer chemotherapy.…”

mentioning

confidence: 99%

Selection of drug-resistant transduced cells with cytosine nucleoside analogs using the human cytidine deaminase gene

et al. 2001

View full text Add to dashboard Cite

Hematopoietic toxicity produced by most anticancer drugs limits their potential for curative therapy. We have shown previously that the human cytidine deaminase ( CD ) gene can confer drug resistance in murine bone marrow cells ( BMCs ) to the nucleoside analog, cytosine arabinoside ( ARA -C ) . In the present study, as the first objective we showed that the CD gene can also render drug resistance in BMCs to related analogs, 2 0 ,2 0 -difluorodeoxycytidine ( dFdC ) and 5 -azadeoxycytidine ( 5 -AZA -CdR ) . As a second objective, we investigated the potential of ex vivo selection with cytosine nucleoside analogs of CD -transduced BMC. The goal of this approach was to enrich the fraction of CD -transduced BMCs so as to increase the transgene expression and level of drug resistance before transplantation. This strategy may have the potential to circumvent the problem in clinical gene therapy of low level of gene transfer and adequate long -term gene expression. Using a bicistronic retroviral vector containing the CD and the green fluorescent protein ( CDiGFP ) , we transduced murine L1210 leukemic cells. All three analogs, ARA -C, dFdC, and 5 -AZA -CdR were demonstrated in vitro to enrich ( > 95% ) the population of leukemic cells expressing the GFP transgene. However, with CD -transduced primary murine BMCs cultivated at high cell density we observed that in vitro selection with ARA -C was not possible due to release of CD into the culture medium at amounts that were sufficient to inactivate the analog. The CD -containing medium produced a chemoprotective effect on mock BMCs as shown by lack of significant growth inhibition in the presence of ARA -C. However, at low cell density in a cell mixture containing CD -transduced cells, the mock BMCs showed marked drug sensitivity to ARA -C as determined by clonogenic assay. Selection with ARA -C was shown to significantly increase the CD enzyme activity in transduced BMC. These results suggest that CD gene has the potential to be a good selectable marker and a possible tool for chemoprotection in cancer gene therapy. Cancer Gene Therapy ( 2001 ) 8, 669 -676

show abstract

In Vivo Drug‐Selectable Genes: A New Concept in Gene Therapy

Cited by 35 publications

References 75 publications

An enhanced EBNA1 variant with reduced IR3 domain for long-term episomal maintenance and transgene expression of oriP-based plasmids in human cells

An enhanced EBNA1 variant with reduced IR3 domain for long-term episomal maintenance and transgene expression of oriP-based plasmids in human cells

Retroviral vector design studies toward hematopoietic stem cell gene therapy for mucopolysaccharidosis type I

Selection of drug-resistant transduced cells with cytosine nucleoside analogs using the human cytidine deaminase gene

Contact Info

Product

Resources

About