Long‐term therapeutic and reporter gene expression in lentiviral vector treated cystic fibrosis mice

Cmielewski, Patricia; Donnelley, Martin; Parsons, David

doi:10.1002/jgm.2778

Cited by 44 publications

(52 citation statements)

References 40 publications

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“…We note that mouse, pig, and human IFITMs also restricted VSV-G-pseudotyped FIV, an envelope that is widely used in gene transfer applications. 5,34 Because it is known that IFITMs restrict entry of other enveloped viruses, including influenza, Ebola, and others, 20-22 our findings likely have broad relevance.…”

Section: Discussionmentioning

confidence: 73%

Human, Pig, and Mouse Interferon-Induced Transmembrane Proteins Partially Restrict Pseudotyped Lentiviral Vectors

Hornick

Oakland

et al. 2016

Human Gene Therapy

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Section: Discussionmentioning

confidence: 73%

Human, Pig, and Mouse Interferon-Induced Transmembrane Proteins Partially Restrict Pseudotyped Lentiviral Vectors

Hornick

Oakland

et al. 2016

Human Gene Therapy

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“…This vector can drive high, stable levels of reporter gene expression in the lungs and nose of mice for the duration of their lifetime (~ 2 yr) and, in contrast to other viral vectors, repeated administration does not lead to loss of efficacy [1–3]. Similar expression profiles using lentivirus-mediated pulmonary gene transfer have been reported by others and are not unique to the F/HN pseudotype [4–6]. The efficacy and toxicity profile of the vector, therefore, supports progression toward the clinic.…”

Section: Introductionmentioning

confidence: 75%

The murine lung as a factory to produce secreted intrapulmonary and circulatory proteins

et al. 2018

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We have shown that a lentiviral vector (rSIV.F/HN) pseudotyped with the F and HN proteins from Sendai virus generates high levels of intracellular proteins after lung transduction. Here, we evaluate the use of rSIV.F/HN for production of secreted proteins. We assessed whether rSIV.F/HN transduction of the lung generates therapeutically relevant levels of secreted proteins in the lung and systemic circulation using human α1-anti-trypsin (hAAT) and factor VIII (hFVIII) as exemplars. Sedated mice were transduced with rSIV.F/HN carrying either the secreted reporter gene Gaussia luciferase or the hAAT or hFVIII cDNAs by nasal sniffing. rSIV.F/HN-hAAT transduction lead to therapeutically relevant hAAT levels (70 μg/ml) in epithelial lining fluid, with stable expression persisting for at least 19 months from a single application. Secreted proteins produced in the lung were released into the circulation and stable expression was detectable in blood. The levels of hFVIII in murine blood approached therapeutically relevant targets. rSIV.F/HN was also able to produce secreted hAAT and hFVIII in transduced human primary airway cells. rSIV.F/HN transduction of the murine lungs leads to long-lasting and therapeutically relevant levels of secreted proteins in the lung and systemic circulation. These data broaden the use of this vector platform for a large range of disease indications.

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“…We have developed an airway gene transfer technique that inserts the corrective gene (CFTR) into defective airway cells of CFTR-null mice, with the resulting CFTR ion-channel correction lasting for at least 12 months [2]. Although we can electrically measure the ionic changes produced by our gene therapy using the established transepithelial potential difference measurement technique, there are currently no methods to rapidly and accurately quantify small corrections in the dysfunctional mucociliary activity or any improvements in airway health in a live animal, after a potential treatment is performed.…”

Section: Introductionmentioning

confidence: 99%

High-resolution mucociliary transport measurement in live excised large animal trachea using synchrotron X-ray imaging

et al. 2017

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BackgroundThe Australian Synchrotron Imaging and Medical Beamline (IMBL) was designed as the world’s widest synchrotron X-ray beam, enabling both clinical imaging and therapeutic applications for humans as well as the imaging of large animal models. Our group is developing methods for imaging the airways of newly developed CF animal models that display human-like lung disease, such as the CF pig, and we expect that the IMBL can be utilised to image airways in animals of this size.MethodsThis study utilised samples of excised tracheal tissue to assess the feasibility, logistics and protocols required for airway imaging in large animal models such as pigs and sheep at the IMBL. We designed an image processing algorithm to automatically track and quantify the tracheal mucociliary transport (MCT) behaviour of 103 μm diameter high refractive index (HRI) glass bead marker particles deposited onto the surface of freshly-excised normal sheep and pig tracheae, and assessed the effects of airway rehydrating aerosols.ResultsWe successfully accessed and used scavenged tracheal tissue, identified the minimum bead size that is visible using our chosen imaging setup, verified that MCT could be visualised, and that our automated tracking algorithm could quantify particle motion. The imaging sequences show particles propelled by cilia, against gravity, up the airway surface, within a well-defined range of clearance speeds and with examples of ‘clumping’ behaviour that is consistent with the in vivo capture and mucus-driven transport of particles.ConclusionThis study demonstrated that the wide beam at the IMBL is suitable for imaging MCT in ex vivo tissue samples. We are now transitioning to in vivo imaging of MCT in live pigs, utilising higher X-ray energies and shorter exposures to minimise motion blur.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-017-0573-2) contains supplementary material, which is available to authorized users.

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Long‐term therapeutic and reporter gene expression in lentiviral vector treated cystic fibrosis mice

Abstract: The present study showed that our airway pre-treatment and gene delivery technique resulted in sustained functional CFTR expression and improved survival in CF mice.

Cited by 44 publications

References 40 publications

Human, Pig, and Mouse Interferon-Induced Transmembrane Proteins Partially Restrict Pseudotyped Lentiviral Vectors

Human, Pig, and Mouse Interferon-Induced Transmembrane Proteins Partially Restrict Pseudotyped Lentiviral Vectors

The murine lung as a factory to produce secreted intrapulmonary and circulatory proteins

High-resolution mucociliary transport measurement in live excised large animal trachea using synchrotron X-ray imaging

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