The developmental stage determines the distribution and duration of gene expression after early intra-amniotic gene transfer using lentiviral vectors

Endo, Masayuki; Henriques‐Coelho, Tiago; Zoltick, Phil W.; Stitelman, David H.; Peranteau, William H.; Radu, Antoneta; Flake, Alan W.

doi:10.1038/gt.2009.115

Cited by 47 publications

(53 citation statements)

References 52 publications

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“…During early gestation while the thymus is processing self-antigen, the fetal immune system can be made tolerant to foreign antigen. In mice, immunological tolerance to viral vector and transgene following in utero gene therapy has provided life-long and stable expression of transgene 15,16 and theoretically, may enable re-administration of the same vector after birth without eliciting an adaptive immune response.…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, HIV-1-based lentiviral vectors (LVs) have increased packaging capacity (optimal transgene insert B5-7 Kb 23 ) and, following in utero delivery, are able to integrate into the host genome to provide life-long stable transgene expression. 16,[24][25][26][27] Fetal lung gene transfer has been investigated in non-human primates, 20,28 rabbits, 29 rats 30,31 and sheep 32 using vesicular stomatitis virus glycoprotein (VSVg) pseudotyped LV. Long-term luciferase transgene expression (that is 12-15 months after fetal gene transfer) has been reported 31,33 although there is a paucity of quantitative information on degree of epithelial transduction and cell types transduced.…”

Section: Introductionmentioning

confidence: 99%

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Jaagsiekte sheep retrovirus pseudotyped lentiviral vector-mediated gene transfer to fetal ovine lung

et al. 2011

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Viral vector-mediated gene transfer to the postnatal respiratory epithelium has, in general, been of low efficiency due to physical and immunological barriers, non-apical location of cellular receptors critical for viral uptake and limited transduction of resident stem/progenitor cells. These obstacles may be overcome using a prenatal strategy. In this study, HIV-1-based lentiviral vectors (LVs) pseudotyped with the envelope glycoproteins of Jaagsiekte sheep retrovirus (JSRV-LV), baculovirus GP64 (GP64-LV), Ebola Zaire-LV or vesicular stomatitis virus (VSVg-LV) and the adeno-associated virus-2/6.2 (AAV2/6.2) were compared for in utero transfer of a green fluorescent protein (GFP) reporter gene to ovine lung epithelium between days 65 and 78 of gestation. GFP expression was examined on day 85 or 136 of gestation (term is B145 days). The percentage of the respiratory epithelial cells expressing GFP in fetal sheep that received the JSRV-LV (3.18Â10 8 -6.85Â10 9 viral particles per fetus) was 24.6 ± 0.9% at 3 weeks postinjection (day 85) and 29.9±4.8% at 10 weeks postinjection (day 136). Expression was limited to the surface epithelium lining fetal airways o100 mm internal diameter. Fetal airways were amenable to VSVg-LV transduction, although the percentage of epithelial expression was low (6.6 ± 0.6%) at 1 week postinjection. GP64-LV, Ebola Zaire-LV and AAV2/6.2 failed to transduce the fetal ovine lung under these conditions. These data demonstrate that prenatal lung gene transfer with LV engineered to target apical surface receptors can provide sustained and high levels of transgene expression and support the therapeutic potential of prenatal gene transfer for the treatment of congenital lung diseases.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Jaagsiekte sheep retrovirus pseudotyped lentiviral vector-mediated gene transfer to fetal ovine lung

et al. 2011

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“…33,34 While some expression of transgene is achieved in the oropharynx and tongue by E8 IAGT, the buccopharyngeal membrane is still intact and prevents access to stem cells in the posterior pharynx and esophagus. 35 Furthermore, the gene expression by E8 IAGT is mostly limited in the epidermal-derived organs. 35 This likely results in poor sucking and feeding by the pups with subsequent death from maternal neglect, cannibalism and/or dehydration.…”

Section: Discussionmentioning

confidence: 99%

“…35 Furthermore, the gene expression by E8 IAGT is mostly limited in the epidermal-derived organs. 35 This likely results in poor sucking and feeding by the pups with subsequent death from maternal neglect, cannibalism and/or dehydration. However, the relatively normal immunohistochemistry findings in combination with failure of the mechanical disruption test suggested that either the expression was quantitatively inadequate to fully correct the skin phenotype, or that the protein was being expressed but was functionally defective.…”

Section: Discussionmentioning

confidence: 99%

Early intra-amniotic gene transfer using lentiviral vector improves skin blistering phenotype in a murine model of Herlitz junctional epidermolysis bullosa

et al. 2011

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Mutations of the LAMB3 gene cause a lethal form of junctional epidermolysis bullosa (JEB). We hypothesized that early intra-amniotic gene transfer in a severe murine model of JEB would improve or correct the skin phenotype. Time-dated fetuses from heterozygous LAMB3 IAP breeding pairs underwent ultrasound guided intra-amniotic injection of lentiviral vector encoding the murine LAMB3 gene at embryonic day 8 (E8). Gene expression was monitored by immunohistochemistry. The transgenic laminin-b3 chain was shown to assemble with its endogenous partner chains, resulting in detectable amounts of laminin-332 in the basement membrane zone of skin and mucosa. Ultrastructually, the restoration of B60% of hemidesmosomal structures was also noted. Although we could correct the skin phenotype in 11.9% of homozygous LAMB3 IAP mice, none survived beyond 48 h. However, skin transplants from treated E18 homozygous LAMB3 IAP fetuses maintained normal appearance for 6 months with persistence of normal assembly of laminin-332. These results demonstrate for the first time long-term phenotypic correction of the skin pathology in a severe model of JEB by in vivo prenatal gene transfer. Although survival remained limited due to the limitations of this mouse model, this study supports the potential for treatment of JEB by prenatal gene transfer.

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“…Pregnant mice were anesthetized and the surgical procedure was performed as previously described 12 with some modifications. Fetuses were scanned using a 30 --70-MHz probe and were positioned to get a clear view of the beating heart in B-mode.…”

Section: In Utero Injection Techniquementioning

confidence: 99%

Early gestational gene transfer with targeted ATP7B expression in the liver improves phenotype in a murine model of Wilson's disease

et al. 2011

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The ideal gene therapy for metabolical liver disorders would target hepatocytes before the onset of disease and be durable, non-toxic and non-immunogenic. Early gestational gene transfer can achieve such goals. Here, we demonstrate that prenatal gene transfer of human Atp7b reduces liver pathology and improves biochemical markers in Atp7b À/À mice, a murine model of Wilson's disease (WD). Following prenatal injection of lentivirus vector containing the human Atp7b gene under the transcriptional control of a liver-specific promoter, the full-length ATP7B was detectable in mouse livers for the entire duration of experiments (20 weeks after birth). In contrast to a marked pathology in non-injected animals, livers from age-matched treated mice consistently demonstrated normal gross and histological morphology. Hepatic copper content was decreased in the majority of treated mice, although remaining copper levels varied. Improvement of hepatic copper metabolism was further apparent from the presence of copper-bound ceruloplasmin in the sera and normalization of the mRNA levels for HMG CoAreductase. With this approach, the complete loss of copper transport function can be ameliorated, as evident from phenotypical improvement in treated Atp7b À/À mice. This study provides proof of principle for in utero gene therapy in WD and other liver-based enzyme deficiencies.

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The developmental stage determines the distribution and duration of gene expression after early intra-amniotic gene transfer using lentiviral vectors

Cited by 47 publications

References 52 publications

Jaagsiekte sheep retrovirus pseudotyped lentiviral vector-mediated gene transfer to fetal ovine lung

Jaagsiekte sheep retrovirus pseudotyped lentiviral vector-mediated gene transfer to fetal ovine lung

Early intra-amniotic gene transfer using lentiviral vector improves skin blistering phenotype in a murine model of Herlitz junctional epidermolysis bullosa

Early gestational gene transfer with targeted ATP7B expression in the liver improves phenotype in a murine model of Wilson's disease

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