(616) CF Gene Therapy: Moving forward

Background: We have previously demonstrated that repeated delivery of a CFTR-liposome (GL67A) complex can stabilise lung function in a double-blind placebo-controlled Phase IIb trial. However, the magnitude of benefit did not warrant continued progression in the context of the welcome benefit provided by small molecule modulators. In parallel, we have developed a lentiviral vector pseudotyped with the Sendai-virus envelope glycoproteins (F/HN) (rSIV.F/HN). We have previously shown that the vector efficiently and persistently transduces airway epithelial cells and in contrast to adenoviral and adeno associated virus-based vectors, retains efficacy on repeated administration.

Methods: In preparation for the first-in-man clinical trial we have carried out a range of non-GLP studies. We (1) assessed transduction in a range of species including non-human primates (NHPs), (2) determined which cell types are transduced, assessed (3) biodistribution of the vector in non-target organs, (4) vector shedding and (5) CFTR function. Lastly, we investigated whether the vector retains efficacy when aerosolised.

Results: Here, we show that rSIV.F/HN transduces airway epithelial cells in mice, rats, sheep and NHPs when administered topically to the lungs, and transduces ciliated, club and goblet cells. Biodistribution studies in mice showed no evidence of non-target organ transduction. Low level of viable vector shedding was detected in nasal lavage fluid for ~24 hrs after dosing. Vector administration to mouse lungs was well tolerated. rSIV.F/HN transduction led to significant iodide efflux and intestinal organoid swelling. Lastly, we showed that the vector retains ≥ 75% transduction efficiency when aerosolised.

Conclusions: This data is supportive for progression towards a first-in-human clinical trial in patients not eligible for CFTR modulator therapies. We have recently completed a licensing deal with Boehringer Ingelheim and GLP-toxicology studies are initiated.

This research was supported in part by Boehringher Ingelheim (BI), and BI was given the opportunity to review this abstract for medical and scientific accuracy, as well as intellectual property considerations.

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