A clinical-stage RNAi therapeutic candidate for IPF mediates durable MMP7 silencing in nonhuman primates and human lung tissue

Introduction: In idiopathic pulmonary fibrosis, matrix metalloproteinase 7 (MMP7) overexpression promotes fibrosis and inflammation and is linked to disease severity. Previous work established that lung-targeted MMP7 siRNAs effectively limit fibrosis and improve function in a rat bleomycin injury model. Here, we determine the expression pattern of MMP7 in response to bleomycin injury and evaluate the pharmacodynamic properties of a clinical-stage RNAi therapeutic candidate (ARO-MMP7) in non-human primates and precision cut lung slices (PCLS). Methods:MMP7 mRNA expression in bleomycin-injured rat lung was determined by RNAscope. Cynomolgus monkeys received inhaled ARO-MMP7 followed by serial BAL collections for 14 weeks to monitor MMP7 expression by immunoassay. Human MMP7 protein expression and enzyme activity was evaluated in human PCLS culture supernatants and AAV6.2FF-CAG-hMMP7 transduced mouse PCLS. Results: We identified aberrant basaloid and club cell populations as the primary source of MMP7 overexpression in the bleomycin-injured rat lung. MMP7 localized to lesions near the BADJ, adjacent to CC10+ epithelial and SPC+ AT2 cells. In primates, ARO-MMP7 reduced BAL MMP7 protein ~80% 2 weeks post-dose with recovery to baseline after 8 weeks. In human PCLS, ARO-MMP7 treatment reduced MMP7 protein and activity. Conclusion: ARO-MMP7, currently in Phase 1/2a trials for the treatment of IPF, effectively silenced BAL MMP7 protein expression in nonhuman primates for over 2 weeks following a single inhaled dose and similarly reduced MMP7 expression in human PCLS, highlighting the value of ex vivo systems for translational validation of siRNA drugs.