Anti-HSP47 siRNA Lipid Nanoparticle ND-L02-s0201 Reverses Interstitial Pulmonary Fibrosis in Preclinical Rat Models

Abstract

ND-L02-s0201 is a lipid nanoparticle encapsulating a siRNA which inhibits expression of heat shock protein 47, a collagen-specific chaperone. Accumulated evidence demonstrates a close association between increased level of HSP47 and excessive accumulation of collagen in fibrotic diseases. Our objective was to test ND-L02-s0201 efficacy in preclinical lung fibrosis models and characterise the downstream histological and functional consequences of inhibiting the expression of HSP47. Comprehensive optimisation and characterisation of bleomycin and silica induced rat lung fibrosis models was conducted, which ensured progressive pathological changes were sustained throughout the study during evaluation of the anti-fibrotic potential of ND-L02-s0201. In the bleomycin model, we demonstrated dose-dependent and statistically significant reduction in lung weight, collagen deposition and histology and fibrosis scores following ND-L02-s0201 treatment. Lung tissue mRNA profiling demonstrated that 11 out of 84 fibrosis relevant genes were upregulated following bleomycin induction and further maximally downregulated approximately four-and-half folds after ND-L02-s0201 treatment. Epithelial-mesenchymal transition was characterised in the bleomycin model following ND-L02-s0201 treatment. Cell enrichment demonstrated myofibroblasts contained the highest HSP47 mRNA expression. Bleomycin led to a more than five-fold increase in myofibroblasts and ND-L02-s0201 treatment reduced the myofibroblasts to Sham levels. Statistically significant improvement in lung function was noted in bleomycin model determined by running endurance capacity using a 7-min treadmill test. Comparable anti-fibrotic efficacy was also observed in the silica model. Results from two robust chronic rodent models of pulmonary fibrosis demonstrated significant anti-fibrotic effects and improved lung function which support the evaluation of ND-L02-s0201 in subjects with idiopathic pulmonary fibrosis.