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

Gene Therapy
Michael C Paul-SmithUta Griesenbach

Abstract

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 sec...Continue Reading

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Citations

Dec 27, 2018·Photochemistry and Photobiology·Svetlana V MarkovaEugene S Vysotski
Aug 5, 2020·Human Gene Therapy·Eric W F W AltonGerry McLachlan
Nov 14, 2020·Experimental Biology and Medicine·Uday K Baliga, David A Dean

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Methods Mentioned

BETA
transfection
enzyme-linked immunosorbent assay
bronchoalveolar
lavage
bronchoalveolar lavage
PCR
Protein Assay
ELISA

Software Mentioned

GraphPad
GraphPad Prism

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