2009
DOI: 10.1038/mt.2009.143
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Biosafety in Ex Vivo Gene Therapy and Conditional Ablation of Lentivirally Transduced Hepatocytes in Nonhuman Primates

Abstract: Ex vivo gene therapy is an interesting alternative to orthotopic liver transplantation (OLT) for treating metabolic liver diseases. In this study, we investigated its efficacy and biosafety in nonhuman primates. Hepatocytes isolated from liver lobectomy were transduced in suspension with a bicistronic liver-specific lentiviral vector and immediately autotransplanted (SLIT) into three cynomolgus monkeys. The vector encoded cynomolgus erythropoietin (EPO) and the conditional suicide gene herpes simplex virus-thy… Show more

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Cited by 28 publications
(19 citation statements)
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“…This metabolite is reminiscent of the metabolite observed by Seppen and colleagues, who showed correction of hyperbilirubinemia in Gunn rats receiving transplantation of cells that do not normally express UGT1A1 but were genetically modified ex vivo to express UGT1A1 (Seppen et al, 1997). It is possible that UGT1A1 expressed in muscle may result in a protein that is not identical to the physiological liverexpressed protein, as previously found in the case of erythropoietin expressed at ectopic sites (Lasne et al, 2004;Menzel et al, 2009). Whether posttranslational modifications of muscle-expressed UGT1A1 play a role in the formation of this unidentified metabolite is unclear at this time.…”
Section: Discussionmentioning
confidence: 65%
“…This metabolite is reminiscent of the metabolite observed by Seppen and colleagues, who showed correction of hyperbilirubinemia in Gunn rats receiving transplantation of cells that do not normally express UGT1A1 but were genetically modified ex vivo to express UGT1A1 (Seppen et al, 1997). It is possible that UGT1A1 expressed in muscle may result in a protein that is not identical to the physiological liverexpressed protein, as previously found in the case of erythropoietin expressed at ectopic sites (Lasne et al, 2004;Menzel et al, 2009). Whether posttranslational modifications of muscle-expressed UGT1A1 play a role in the formation of this unidentified metabolite is unclear at this time.…”
Section: Discussionmentioning
confidence: 65%
“…These data corroborate previous reports demonstrating long-term liver-specific activity of the mTTR promoter in vivo. 37,42 Moreover, the results indicate that the mTTR promoter is suitable for longterm hepatospecific expression of HBV-targeting artificial pri-miRs.…”
Section: Resultsmentioning
confidence: 92%
“…In this study, the results have shown a lack of toxicity and persistent gene expression lasting at least four months following gene therapy. Successful reports of human hepatocyte genetic correction, using lentiviral vectors, followed by transplantation in the Gunn rat [94] [10,92] and nonhuman primates [82] have been published. These findings confirm the potential feasibility of gene therapy by using lentiviral vectors to treat liver-based inborn errors of metabolism, which are a prerequisite to clinical applications (for review see [93]).…”
Section: Human Ips Cell Therapies For Hereditary Metabolic Liver Disementioning
confidence: 99%