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ARO-ENaC rat poster...

Targeting aENaC with an Epithelial RNAi Trigger Delivery Platform for the Treatment of Cystic Fibrosis

CONCLUSIONS

•EpLintegrin avb6 receptor ligands improve endocytosis of RNAi triggers in cultured epithelial cells

•EpLconjugates employing ligands to the integrin avb6 receptor improve functional delivery of an aENaCRNAi trigger to the pulmonary epithelium after inhalation, producing deeper and more consistent reduction of whole lung aENaCmRNA at lower doses

•Loss of airway epithelial aENaCprotein expression is observed at exposures that produce ~50% reduction in whole lung aENaCmRNA, with remaining protein expressed in alveolar epithelium

•Reduction of lung aENaCmRNA expression is durable, maintaining >50% knockdown at 3 weeks post-dose and requiring 6-7 weeks for recovery to baseline expression

•Aerosol inhalation improves delivery efficiency of EpL-aENaCRNAi trigger conjugates approximately tenfold over intratracheal administration

•EpL-aENaCRNAi trigger conjugates are well-tolerated with no observed changes in renal aENaCmRNA expression