WS17.06 F/HN pseudotyped lentiviral vector-mediated transduction of non-human primates

Objectives: 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. We have previously demonstrated restoration of CFTR function 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. We have now assessed transduction efficiency and acute toxicology in non-human primates (NHPs). Methods: Male cynomolgus monkeys received a single dose of aerosolised rSIV.F/HN vector expressing green fluorescent protein (GFP) (4.2e9 transduction units in ~2 ml) or placebo via an endotracheal tube (n = 3/group). Approximately 25% of the dose (mass median aerodynamic diameter 3.9 µm) was deposited in the lungs. Toxicology was assessed by histopathology, clinical pathology, cytokine levels and changes in body and organ weight, and transduction efficiency was quantified by GFP immunohistochemistry and vector-specific mRNA 7 days post-dosing. Results: There were no vector-related clinical observations, mortality, or changes in body or organ weight. Clinical pathology and cytokine analyses were unremarkable. A 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 higher than endogenous CFTR mRNA levels. Conclusions: This study confirms and extends our previous findings of rSIV.F/HN-based in vivo gene transfer in mice to NHPs. Using a relatively low vector dose, NHPs demonstrated transduction efficiency in the range of values likely to relate to clinical benefit, without evidence of toxicity. Transduction efficiency and toxicology in animals treated with a higher dose is currently being analysed. These data, together with our previous murine data, support further progression of BI 3720931 towards the clinic.