F/HN-pseudotyped lentiviral vector efficiently transduces non-human primate airways with no evidence of relevant...

We have developed a third-generation lentiviral vector pseudotyped with Sendai virus F and HN envelope proteins (rSIV.F/HN) expressing functional cystic fibrosis transmembrane conductance regulator (CFTR) as a gene therapy for cystic fibrosis (BI 3720931). Here, we assessed transduction efficiency and acute toxicology of the rSIV.F/HN vector expressing an enhanced green fluorescent protein (EGFP) reporter gene in non-human primates (NHPs). Intubated male cynomolgus monkeys received one aerosolized dose of vector (n = 3) or placebo (n = 3). Toxicology was assessed by histopathology, clinical pathology, cytokine levels, and changes in body and organ weight. Transduction efficiency was quantified by EGFP immunohistochemistry in airway epithelial cells and vector-specific mRNA and DNA in the lung 7 days post-dosing. There were no vector-related clinical observations, mortalities, or changes in body or organ weight. Clinical pathology and cytokine analyses were unremarkable. Minimal mixed-cell centriacinar inflammation was observed in 1/3 vector-treated animals. Airway epithelial cell transduction efficiency was 9%-12%. Genomic DNA vector integration was detected in 6.7% of lung epithelial cells. Vector-specific mRNA levels were ∼45× endogenous CFTR mRNA levels in lung epithelium and ∼16× in bronchial brushings. This study extends earlier findings of rSIV.F/HN-based in vivo gene transfer in mice to NHPs, demonstrating transduction efficiency without relevant toxicity.