An antisense oligonucleotide targeting HSPB5 as an innovating therapeutic approach in pulmonary fibrosis

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Introduction: Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by fibroblasts activation and abnormal extracellular-matrix accumulation withit the lungs. We previously demonstrated the importance of heat shock protein αB-crystallin (HSPB5) in the transforming-growth-factor (TGF)-β1 profibrotic signaling, which suggest that HSPB5 could be a new therapeutic target for the treatment of pulmonary fibrosis. The purpose of the current study was to develop antisense oligonucleotides targeting HSPB5 and study their effects on the development of experimental pulmonary fibrosis. Methods: Specific antisense oligonucleotides (ASO) were designed and screened in vitro, based on their ability to inhibit both human and murine HSPB5 expression. The selected ASO22 was characterized in vitro in human fibroblast CCD-19Lu cells and in A549 epithelial pulmonary cells as well as in a mouse model of bleomycin-induced pulmonary fibrosis. Results: We identified an ASO based on its capacity to inhibit the TGF-β1-induced expression of HSPB5 and additional key markers of fibrosis such as PAI-1, collagen, fibronectin and α-SMA in fibroblastic human CCD-19Lu cells as well as PAI-1 and α-SMA in pulmonary epithelial A549 cells. In the bleomycin model, our ASO either injected intra-tracheally or intravenously, potently decreased HSPB5 expression and inhibited fibrosis development as measured by the decrease in pulmonary remodeling, collagen accumulation and Acta2 and Col1a1 expression. Conclusion: Altogether, our results suggest a real interest of using an antisense oligonucleotide strategy targeting HSPB5 for the treatment of pulmonary fibrosis.

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