Background Stabilized-release caprine corticotrophin releasing hormone-1 (SR-CCRH-1) is held in a multi-protein complex and derived from hyperimmune caprine sera (HICS). SR-CCRH-1 may have an efficacy trait and accordingly warranted investigation.
Objectives The objective of the study was to determine whether a novel stabilized-release caprine corticotrophin releasing hormone-1 (SR-CCRH-1) neuropeptide could elicit measurable efficacy as an anti-fibrotic agent in the murine bleomycin (BLM)-induced skin fibrosis model (an in vivo study model used to demonstrate the therapeutic effects of test articles on cutaneous fibrosis and inflammation).
Methods For this study, age-sex-matched C57BL/6 male and female mice, n=8-12 per treatment group (saline control, naïve serum control, bleomycin/saline, bleomycin/naïve and bleomycin/SR-CCRH-1), were injected daily with (100 μg s.c.) of SR-CCRH-1 or naïve serum in the respective group using a double-blind experimental protocol for 50 days. Study mice were administered with 0.09 units of BLM in 50 μl volume by s.c. injection on alternate days for 50 days.
Results The results showed that on examination of immunohistochemical staining of skin biopsies [taken from sections from each group (n=6)] using H&E, Masson's Trichrome, a-skeletal muscle actin and thrombin, that SR-CCRH-1 significantly inhibited cutaneous fibrosis (p<0.05), inflammatory cellular infiltrate (p=0.051), epidermal thickening (p=0.012) and reduced ulcer formation marginally (p=0.093) in the BLM/SR-CCRH-1 group relative to control groups. ELISA studies from skin homogenates further confirmed and showed that SR-CCRH-1 significantly reduced the hydroxyproline content (p=0.0133) and lipoprotein related peptide-1 (p=0.009) levels in the skin of animals treated with BLM.
A significant increase in a-melanocyte-stimulating hormone (p=0.003), a cleavage product of pro-opiomelanocortin was also noted. The mechanism of action appeared to revolve around a CRH-1- (p=0.0027) and not CRH-2-mediated response.
Skin homogenates showed that MC-4R a target of a-MSH (but not MC-1R) appeared to be significantly involved as a downstream target (p=0.017). MMP-9 (p=0.019), MMP-1 (p=0.058), MMP-13 (p=0.038) and PIIINP (p<0.05) were also significantly reduced in the SR-CCRH-1 treated BLM mice vs BLM-treated controls. ELISA studies on serum taken from the study groups further confirmed significant inhibition of MMP-9 (p=0.0291) and a change in TIMP1 (p=0.058).
Conclusions The study taken together provides a novel targeted approach that focused on the CRH-1 receptor expressed in the skin and hypothalamo-pituitary-adrenal axis that led to a cascade of changes highlighted by abrogation of inflammation and cutaneous fibrosis. SR-CCRH-1 may serve as a potential therapeutic in the treatment of cutaneous fibrotic disease. To that end, in a recently completed phase II double blind placebo controlled trial in established late-stage diffuse systemic sclerosis using SR-CCRH-1 pointed to an efficacy signal with reduced a Modified Rodnan Skin Score, and a favourable safety/tolerability profile.
Disclosure of Interest J. Woloszynek: None declared, K. Etzel: None declared, J. Vernes Employee of: employee, D. McIntosh Shareholder of: Shareholder, Consultant for: Consultant, C. Moore Shareholder of: Shareholder, M. Haq Shareholder of: Shareholder, H. Lopez: None declared, S. Haq Shareholder of: Director
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