Development of Lentiviral Vectors with Regulated Respiratory Epithelial Expression <i>In Vivo</i>

Hendrickson, Benjamin; Senadheera, Dinithi; Mishra, Suparna; Bui, Kevin; Wang, Xingchao; Chan, Belinda; Petersen, Denise; Pepper, Karen; Lutzko, Carolyn

doi:10.1165/rcmb.2006-0276oc

Cited by 15 publications

(12 citation statements)

References 51 publications

(57 reference statements)

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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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“…More recently, adenoviruses using Scgb1a1 , rat SftpC , or rat CGRP promoter fragments to direct Cre expression to specific epithelial cell types have been developed [134]. Lentiviral vectors containing specific promoters for manipulating gene expression in restricted adult lung epithelial cell types have also been reported [180, 181]. In addition, Adeno-Associated Virus (AAV) transduction of mouse lung epithelial progenitors has also been demonstrated [182].…”

Section: The Jackson Laboratories Websitementioning

confidence: 99%

The a“MAZE”ing World of Lung-Specific Transgenic Mice

Rawlins

Perl

2012

Am J Respir Cell Mol Biol

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The purpose of this review is to give a comprehensive overview of transgenic mouse lines suitable for studying gene function and cellular lineage relationships in lung development, homeostasis, injury and repair. Many of the mouse strains reviewed in this article have been widely shared within the lung research community and new strains are continuously being developed. There are many useful transgenic lines that work to target subsets of lung cells, but it remains a challenge for investigators to select the correct transgenic modules for their experiment. This review covers both the tetracycline and tamoxifen inducible systems and will primarily focus on conditional lines that target the epithelial cells. We point out the limitations of each strain so investigators can choose the system that will work best for their scientific question. Current mesenchymal and endothelial lines are limited by the fact that they are not lung specific. These lines will be summarized in a brief overview. In addition, useful transgenic reporter mice for studying lineage relationships, promoter activity and signaling pathways will complete our lung specific conditional transgenic mouse-shopping list.

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“…Immunohistochemistry was performed as described with an antihuman ADA monoclonal antibody (N-19; Santa Cruz Biotechnology). 31 …”

Section: Necropsy Tissue Harvest and Immunohistochemical Analysismentioning

confidence: 99%

Gene therapy/bone marrow transplantation in ADA-deficient mice: roles of enzyme-replacement therapy and cytoreduction

Carbonaro

Jin

Wang

et al. 2012

Blood

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AbstractGene therapy (GT) for adenosine deaminase–deficient severe combined immune deficiency (ADA-SCID) can provide significant long-term benefit when patients are given nonmyeloablative conditioning and ADA enzyme-replacement therapy (ERT) is withheld before autologous transplantation of γ-retroviral vector-transduced BM CD34+ cells. To determine the contributions of conditioning and discontinuation of ERT to the therapeutic effects, we analyzed these factors in Ada gene knockout mice (Ada−/−). Mice were transplanted with ADA-deficient marrow transduced with an ADA-expressing γ-retroviral vector without preconditioning or after 200 cGy or 900 cGy total-body irradiation and evaluated after 4 months. In all tissues analyzed, vector copy numbers (VCNs) were 100- to 1000-fold greater in mice receiving 900 cGy compared with 200 cGy (P < .05). In mice receiving 200 cGy, VCN was similar whether ERT was stopped or given for 1 or 4 months after GT. In unconditioned mice, there was decreased survival with and without ERT, and VCN was very low to undetectable. When recipients were conditioned with 200 cGy and received transduced lineage-depleted marrow, only recipients receiving ERT (1 or 4 months) had detectable vector sequences in thymocytes. In conclusion, cytoreduction is important for the engraftment of gene-transduced HSC, and short-term ERT after GT did not diminish the capacity of gene-corrected cells to engraft and persist.

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Development of Lentiviral Vectors with Regulated Respiratory Epithelial Expression In Vivo

Cited by 15 publications

References 51 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

The a“MAZE”ing World of Lung-Specific Transgenic Mice

Gene therapy/bone marrow transplantation in ADA-deficient mice: roles of enzyme-replacement therapy and cytoreduction

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