Lentivirus vector‐mediated gene transfer to the developing bronchiolar airway epithelium in the fetal lamb

Yu, Ze‐Yan; McKay, Karen; Asperen, Peter Van; Zheng, Maolin; Fleming, Jane; Ginn, Samantha L.; Kizana, Eddy; Latham, Margot; Feneley, Michael P.; Kirkland, Peter D.; Rowe, Peter B.; Lumbers, Eugenie R.; Alexander, Ian E.

doi:10.1002/jgm.1039

Cited by 25 publications

(21 citation statements)

References 46 publications

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“…Receptors for the VSV-G envelope are thought to be sequestered on the basolateral surface of adult lung epithelia, preventing their in vivo transduction in the absence of epithelial injury in most prior reports (13)(14)(15)(16). However, VSV-Gpseudotyped lentiviral vectors do appear to possess some capacity to transduce lung epithelial cells in vitro (49,50), when administered in vivo at early fetal developmental stages (51,52), or when delivered together with epithelial mitogens such as KGF (53). Alternatively, lentiviral vectors pseudotyped with other viral envelope glycoproteins such as Ebola do appear to possess adult lung epithelial tropism in vivo (13,15,52,54).…”

Section: Discussionmentioning

confidence: 99%

Amelioration of emphysema in mice through lentiviral transduction of long-lived pulmonary alveolar macrophages

Wilson

Murphy²,

Hamakawa³

et al. 2010

J. Clin. Invest.

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Directed gene transfer into specific cell lineages in vivo is an attractive approach for both modulating gene expression and correcting inherited mutations such as emphysema caused by human α1 antitrypsin (hAAT) deficiency. However, somatic tissues are mainly comprised of heterogeneous, differentiated cell lineages that can be short lived and difficult to specifically transfect. Here, we describe an intratracheally instilled lentiviral system able to deliver genes selectively to as many as 70% of alveolar macrophages (AMs) in the mouse lung. Following a single in vivo lentiviral transduction, genetically tagged AMs persisted in lung alveoli and expressed transferred genes for the lifetime of the adult mouse. A prolonged macrophage lifespan, rather than precursor cell proliferation, accounted for the surprisingly sustained presence of transduced AMs. We utilized this long-lived population to achieve localized secretion of therapeutic levels of hAAT protein in lung epithelial lining fluid. In an established mouse model of emphysema, lentivirally delivered hAAT ameliorated the progression of emphysema, as evidenced by attenuation of increased lung compliance and alveolar size. After 24 weeks of sustained gene expression, no humoral or cellular immune responses to hAAT protein were detected. Our results challenge the dogma that AMs are short lived and suggest that these differentiated cells may be a possible target cell population for in vivo gene therapy applications, including the sustained correction of hAAT deficiency.

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Section: Discussionmentioning

confidence: 99%

Amelioration of emphysema in mice through lentiviral transduction of long-lived pulmonary alveolar macrophages

Wilson

Murphy²,

Hamakawa³

et al. 2010

J. Clin. Invest.

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“…11 In our experience, optimal transduction time of 293T cells with JSRV-and VSVg-LV requires a minimum of 48 h. Previous sheep studies that examined retroviral gene transfer to the fetal lung did not occlude the fetal trachea at the time of intra-tracheal vector administration, which may explain, in part, limited transduction of airway epithelium compared with that of our current sheep study. 32,46 Another potential advantage of performing tracheal occlusion following intra-tracheal administration of vector is to enhance epithelial transduction via increased proliferation. Fetal tracheal occlusion rapidly increases lung epithelial proliferation, 47 while increased cell cycling has been shown to enhance lentiviral transduction in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…In sheep, VSVg-LV injected into the fetal airways between days 75 and 77 achieved limited airway epithelial transduction. 32 The receptor for VSVg is thought to be located on the basolateral surface of the respiratory epithelium, 34,35 which may explain, in part, inefficient gene transfer to the fetal respiratory epithelium in sheep. 32 Designing pseudotyped LV to target airway epithelial surface receptors is an effective strategy to enhance lung gene transfer.…”

Section: Introductionmentioning

confidence: 99%

“…32 The receptor for VSVg is thought to be located on the basolateral surface of the respiratory epithelium, 34,35 which may explain, in part, inefficient gene transfer to the fetal respiratory epithelium in sheep. 32 Designing pseudotyped LV to target airway epithelial surface receptors is an effective strategy to enhance lung gene transfer. [36][37][38] To determine whether a lung-targeting vector would efficiently transduce fetal sheep airways, we developed a LV pseudotyped with the envelope glycoprotein of the Jaagsiekte sheep retrovirus (JSRV).…”

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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“…This resulted in transduction of the lung parenchyma, although the airway epithelium was not transduced in this approach. In contrast, a number of rodent and large animal studies have demonstrated the transduction of respiratory epithelium after lentiviral supernatant gene delivery to the amniotic fluid (15)(16)(17)(18)(19). In this strategy, normal fetuses inhale and swallow the amniotic fluid, providing the vector access to the airways and digestive system.…”

mentioning

confidence: 99%

Genetic Modification of Airway Progenitors after Lentiviral Gene Delivery to the Amniotic Fluid of Murine Fetuses

Mishra¹,

Wang²,

Smiley³

et al. 2011

Am J Respir Cell Mol Biol

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Lentivirus vector‐mediated gene transfer to the developing bronchiolar airway epithelium in the fetal lamb

Cited by 25 publications

References 46 publications

Amelioration of emphysema in mice through lentiviral transduction of long-lived pulmonary alveolar macrophages

Amelioration of emphysema in mice through lentiviral transduction of long-lived pulmonary alveolar macrophages

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

Genetic Modification of Airway Progenitors after Lentiviral Gene Delivery to the Amniotic Fluid of Murine Fetuses

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