Genetic protection of repopulating hematopoietic cells with an improved <i>MDR1</i>‐retrovirus allows administration of intensified chemotherapy following stem cell transplantation in mice

Carpinteiro, Alexander; Peinert, Stefan; Ostertag, Wolfram; Zander, Axel R.; Hossfeld, Dieter K.; Kühlcke, Klaus; Eckert, Hans-Georg; Baum, Christopher; Hegewisch‐Becker, Susanna

doi:10.1002/ijc.10206

Cited by 27 publications

(9 citation statements)

References 47 publications

(72 reference statements)

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“…Numerous studies, including a transgenic mouse model, have shown the ability to overexpress MDR1 in hematopoietic cells without overt alterations of cell functions (other than the acquired drug-resistance phenotype). 85,134,135,139,140 Applications in dogs, 141 nonhuman primates, 110 and clinical trials 45,46,142 have been safe, with occasional evidence for increased pump activity, although gene transfer efficiency was likely very low.…”

Section: Murine Leukemia Following Mdr1 Gene Transfer: Phenotoxicitymentioning

confidence: 99%

Side effects of retroviral gene transfer into hematopoietic stem cells

Baum

Düllmann

et al. 2003

Blood

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384

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Recent conceptual and technical improvements have resulted in clinically meaningful levels of gene transfer into repopulating hematopoietic stem cells. At the same time, evidence is accumulating that gene therapy may induce several kinds of unexpected side effects, based on preclinical and clinical data. To assess the therapeutic potential of genetic interventions in hematopoietic cells, it will be important to derive a classification of side effects, to obtain insights into their underlying mechanisms, and to use rigorous statistical approaches in comparing data. We here review side effects related to target cell manipulation; vector production; transgene insertion and expression; selection procedures for transgenic cells; and immune surveillance. We also address some inherent differences between hematopoiesis in the most commonly used animal model, the laboratory mouse, and in humans. It is our intention to emphasize the need for a critical and hypothesis-driven analysis of "transgene toxicology," in order to improve safety, efficiency, and prognosis for the yet small but expanding group of patients that could benefit from gene therapy. (Blood. 2003;

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Section: Murine Leukemia Following Mdr1 Gene Transfer: Phenotoxicitymentioning

confidence: 99%

Side effects of retroviral gene transfer into hematopoietic stem cells

Baum

Düllmann

et al. 2003

Blood

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384

241

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“…Some researchers found that the success of high-dose chemotherapy (HDCT) and hematopoietic stem cell transplantation in the treatment of malignancies would achieve long term complete responses because of the dose-response relationship. [5,6]…”

Section: Introductionmentioning

confidence: 99%

Evaluation of biodistribution and safety of adenovirus vector containing MDR1 in mice

Zhao

Liu

et al. 2010

J Exp Clin Cancer Res

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BackgroundThe aim of this study is to examine the safety and distribution of Ad-EGFP-MDR1, an adenovirus encoding human multidurg resistance gene (human MDR1), in the mice colon carcinoma model.MethodsAfter bone marrow cells (BMCs) were infected with Ad-EGFP-MDR1, they were administered by intra bone marrow-bone marrow transplantation (IBM-BMT). Total adenovirus antibody and serum adenovirus neutralizing factor (SNF) were determined. Biodistribution of Ad-EGFP-MDR1 was detected by in situ hybridization and immunohistochemistry. The peripheral hematocyte white blood cell (WBC), haemoglobin (Hb), red blood cell (RBC) and platelet (Plt) counts were analyzed.ResultsNeither total adenovirus antibody nor SNF increased weeks after BMT. In situ hybridization and immunohistochemistry demonstrated concordant expression of human MDR1 and P-gp which were found in lung, intestine, kidney and BMCs after BMT, but not detected in liver, spleen, brain and tumor. No significant abnormality of the recovery hematocyte was observed on Day 30 after treatment.ConclusionThe results indicate that IBM-BMT administration of a replication defective adenovirus is a feasible mode of delivery, allowing exogenous transference. The findings in this study are conducted for the future long-term studies of safety assessment of Ad-EGFP-MDR1.

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“…4 However, the use of retroviral MDR1 vectors encoding the 'splicecorrected' cDNA from a backbone derived from the Harvey murine sarcoma virus (HaMSV) was complicated by the occurrence of myeloproliferative disorders in mice transplanted with gene-modified hematopoietic cells, 5,6 while these disorders were not observed with vectors containing the wild-type cDNA. 2,7,8 The myeloproliferative disease was associated with a high copy number of retroviral MDR1 transgenes in transformed cells, 6 while it was not seen in monkeys transduced with a low copy number of the vector. 9 Clinical trials, conducted with vectors encoding 'uncorrected' MDR1, showed no evidence for vector-related toxicity; however, they were hampered by an incomplete expression of the multidrug-resistant phenotype.…”

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confidence: 99%

Impact of splice-site mutations of the human MDR1 cDNA on its stability and expression following retroviral gene transfer

et al. 2003

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The multidrug resistance 1 (MDR1) gene transfer to hematopoietic cells for protection against cytotoxic drugs has received considerable attention in gene therapy. However, ectopic expression of MDR1 from retroviral vectors has been hampered by its genetic instability resulting from cryptic splice sites within the cDNA. We have evaluated the efficiency of retroviral MDR1 vectors with introduced mutations of the MDR1 cryptic splice donor (cSD) located at nucleotide +339 and of the cryptic splice acceptor (cSA) at nucleotide +2319 of the cDNA. Sequence alterations of the cSD reduced the expression of MDR1 P-glycoprotein (P-gp), even when generated as silent mutations. A silent mutation of the cSA reduced the splicing activity shifting the splice acceptor site one base downstream; however, it significantly improved the expression of P-gp. The incidence of wild-type MDR1 pregenome splicing was markedly reduced when vectors were produced in human 293 packaging cells as opposed to murine PG13 and GP+envAm12. We conclude that complete splice correction of MDR1 in retroviral vectors may only be achieved with extensive alterations of the cDNA or neighboring vector sequences and that the splicing is significantly influenced by the choice of the packaging cells.

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Genetic protection of repopulating hematopoietic cells with an improved MDR1‐retrovirus allows administration of intensified chemotherapy following stem cell transplantation in mice

Cited by 27 publications

References 47 publications

Side effects of retroviral gene transfer into hematopoietic stem cells

Side effects of retroviral gene transfer into hematopoietic stem cells

Evaluation of biodistribution and safety of adenovirus vector containing MDR1 in mice

Impact of splice-site mutations of the human MDR1 cDNA on its stability and expression following retroviral gene transfer

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