P131 Cellular communication network factor (CCN3)-derived peptide BLR200 impairs bleomycin-induced lung fibrosis

Scleroderma (systemic sclerosis; SSc) is an autoimmune connective tissue disease characterized by progressive fibrosis of the skin and internal organs. Lung fibrosis is a significant cause of mortality in SSc. Alterations in the expression of members of the cellular communication network (CCN) family of matricellular proteins are a hallmark of SSc. Of the CCN family, CCN2 is profibrotic and CCN3 is antifibrotic. We have developed a CCN3-derived peptide, BLR-200, as an anti-fibrotic therapeutic. BLR-200 has been given orphan drug designation by the US Food and Drug Administration. Whether BLR-200 has antifibrotic activity in a model of SSc lung fibrosis is unknown.

We use Western blot analysis to assess CCN3 expression levels in fibroblasts from healthy individuals and individuals with SSc. We use the bleomycin model (one dose of bleomycin, injected intratracheally at d0) of lung fibrosis (the industry-standard method of assessing experimental SSc lung fibrosis) to assess the effect of BLR-200 (subcutaneous injection, 3 times/week, over 21 days) on histological and molecular markers of lung fibrogenesis.

CCN3 protein expression is reduced in SSc fibroblasts (N = 3, p < 0.05). Injection of BLR-200, compared to control scrambled peptide, significantly attenuated bleomycin-induced lung fibrosis, as visualized by histological (Ashcroft score of Trichrome-stained sections), protein (hydroxyproline collagen assay), lung weight, and mRNA (expression of CCN1, CCN2, COL1A2, ACTA2, PLOD2 as assessed by real-time polymerase chain reaction) analyses (all N = 5, all p < 0.05).

As BLR-200 reduces bleomycin-induced lung fibrosis, BLR-200 may represent a novel treatment for SSc lung fibrosis.

P. Chitturi: None. S. Xu: None. R.J. Stratton: None. B.L. Riser: Corporate appointments; CEO, BLR Bio, LLC. A. Leask: Grants/research support; Canadian Institutes of Health Research.