Anti-HSP47 siRNA lipid nanoparticle ND-L02-s0201 reverses interstitial pulmonary fibrosis in preclinical rat models. Issue 2 (7th June 2021)

• Record Type: Journal Article
• Authors: Liu, Yun; Liu, Jian; Quimbo, Alistair; Xia, Fengcheng; Yao, Jiping; Clamme, Jean-Pierre; Zabludoff, Sonya; Zhang, Jun; Ying, Wenbin
• Is Part Of: ERJ open research. Volume 7:Issue 2(2021)
• Publication Date: 2021-06-07
• Subjects: Respiratory organs -- Diseases -- Periodicals; Respiration -- Periodicals; Respiration; Respiratory organs -- Diseases; Respiratory organs -- Diseases -- Treatment; Respiratory Tract Diseases; Electronic journals; Fulltext; Internet Resources; Periodicals; Periodical; 616.2005
• DOI: 10.1183/23120541.00733-2020
• Languages: English
• ISSNs: 2312-0541

Abstract

ND-L02-s0201 is a lipid nanoparticle encapsulating an siRNA which inhibits expression of heat shock protein 47 (HSP47), 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 (BLM) and silica-induced rat lung fibrosis models were conducted, which ensured progressive pathological changes were sustained throughout the study during evaluation of the anti-fibrotic potential of ND-L02-s0201. In the BLM model, we demonstrated dose-dependent and statistically significant reduction in the relative 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 BLM induction and were downregulated by approximately 4.5-fold following ND-L02-s0201 treatment. Epithelial–mesenchymal transition was characterised in the BLM model following ND-L02-s0201 treatment. Cell enrichment demonstrated that myofibroblasts contained the highest HSP47 mRNA expression. BLM led to more than a 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 the BLM model which was determined by running endurance capacity using a 7-minute 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. By targeting HSP47 and facilitating normalisation of EMT, siRNA lipid nanoparticle ND-L02-s0201 reverses interstitial pulmonary fibrosis, restores structural integrity of the lung, and improves pulmonary function in preclinical rat models. https://bit.ly/3a2lo1B