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F/HN-pseudotyped lentiviral vector-mediated transduction of non-human primates

U Griesenbach(1) G McLachlan(2) A Sinadinos(1) C Cheminay(3) J Ashour(3) C Meng(1) E Castells(4) R Dean(4) M A Viegas(4) A C Boyd(5) J C Davies(1) D R Gill(4) S C Hyde(4) D Blanset(3) E WFW Alton(1)

1:National Heart and Lung Institute, Imperial College London; 2:The Roslin Institute, University of Edinburgh; 3:Boehringer Ingelheim Pharmaceuticals, Inc.; 4:Radcliffe Department of Medicine, University of Oxford; 5:Centre for Genomic and Experimental Medicine, University of Edinburgh


We have developed a lentiviral vector platform pseudotyped with the Sendai virus F and HN envelope proteins (rSIV.F/HN), including the clinical candidate BI 3720931 for cystic fibrosis (CF) gene therapy. Previously, we demonstrated efficacy in CF-patient bronchial epithelial cell air–liquid interface cultures and intestinal organoids, as well as efficient and persistent in vivo transduction of murine airways. Here we assess transduction efficiency and acute toxicology in non-human primates (NHPs).


Male cynomolgus monkeys received a single dose of rSIV.F/HN vector expressing green fluorescent protein (GFP) (4.2e9 transduction units) or placebo via an endotracheal tube (n=3/group), achieving lung deposition of ~25%. Toxicology was assessed by histopathology, clinical pathology, cytokine levels and changes in body and organ weight; transduction efficiency was quantified by analysing vector-specific mRNA 7 days post dosing.


There were no vector-related clinical observations, mortality, or changes in body or organ weight. Clinical pathology and cytokine analyses were unremarkable. Minimal mixed-cell centriacinar inflammation was observed in 1/3 active-treated animals. Airway epithelial cell transduction efficiency was 9–12% and vector-specific mRNA levels were ~45x endogenous cystic fibrosis transmembrane conductance regulator mRNA levels.


This study extends our findings of rSIV.F/HN-based in vivo gene transfer in mice to NHPs, demonstrating transduction efficiency in the range likely to relate to clinical benefit, without toxicity. Animals treated with a higher dose are currently being analysed. These data, together with our previous murine data, support further progression of BI 3720931 towards the clinic.

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