Anti-fibrotic therapy for primary sclerosing cholangitis Abstract Primary sclerosing cholangitis (PSC) is a rare and severe condition in which chronic bile duct injury leads to liver fibrosis. Currently, there are no approved therapeutics for PSC, and the only definitive cure is liver transplant. Hence, an urgent need exists to find effective treatments, particularly interventions that can prevent, reduce, and potentially reverse liver fibrosis. H2 relaxin (serelaxin) acts on the G protein-coupled receptor (GPCR), Relaxin Family Peptide Receptor 1 (RXFP1) to mediate vasodilatory and cardioprotective effects in patients with acute heart failure (AHF). However, the long-term beneficial effects of serelaxin in AHF are likely related to its strong anti-fibrotic effects that have been shown in animal models of multiple diseases involving fibrosis, including cardiac, pulmonary, renal, and hepatic. Recent data suggest that serelaxin may be a promising treatment for diseases characterized by fibrosis. Despite its enormous potential, serelaxin has a short half-life in vivo, is difficult to synthesize, and cross-reacts with the related receptor, RXFP2. In addition, the cAMP-mediated actions of serelaxin may be associated with deleterious long-term effects. To address these limitations, we have identified a novel B-chain-only peptide variant of serelaxin, B7-33, which is RXFP1-specific and ameliorates fibrosis via cell-specific effects on fibroblasts. B7-33 is less expensive to manufacture, and as a single chain peptide is also far easier to functionalize to improve its stability and in vivo efficacy. We have prepared a lipidated B7-33 with an extended plasma half-life. B7-33 is the first single-chain insulin-like peptide having a selective signaling profile that favors the anti-fibrotic actions of serelaxin, but with minimal cAMP-related effects. The overall goal of this project is to develop and characterize B7-33 as an innovative treatment for PSC. In Phase 1, we will confirm biological activity in vitro and evaluate B7-33 in a small animal model of PSC. Significant attenuation of fibrosis in the animal model will merit submission of a Phase 2 application. Phase 2 work will focus on obtaining the preclinical data necessary for submission of an IND. Pharmacokinetics and toxicity studies, as well as animal studies to demonstrate efficacy, will be performed.
Public Health Relevance Statement: Narrative Primary sclerosing cholangitis (PSC) is a progressive chronic liver disease characterized by hepatic inflammation and fibrosis that lead to multifocal biliary strictures. PSC is closely associated with inflammatory bowel disease that is present in a majority of the patients. Most patients will require liver transplantation, which is often not curative due to disease recurrence. There is no approved treatment for PSC, despite recent advances in understanding the cause of the disease. The purpose of this proposal is to develop a new therapy for PSC with a novel mechanism of action to prevent fibrosis.
Project Terms: Acute; Address; analog; angiogenesis; Animal Model; Animals; assay development; Attenuated; attenuation; base; bile duct; Biliary; Binding; Biochemistry; Biological; Biological Assay; Cardiac; cardioprotection; Cells; cholangiocyte; Chronic; chronic liver disease; Collaborations; Collagen; Cyclic AMP; Data; design; Disease; Disease Progression; Dose; Drug Kinetics; effective therapy; Family; Fibroblasts; Fibrosis; G-Protein-Coupled Receptors; Goals; Half-Life; Heart failure; Hepatic; Hepatic Stellate Cell; Hormones; Human; improved; in vitro activity; in vivo; Inflammation; Inflammatory Bowel Diseases; Injury; innovation; Insulin; Intervention; Kidney; Lead; Letters; Lipids; Liver Cirrhosis; Liver Fibrosis; liver transplantation; Long-Term Effects; Lung; Matrix Metalloproteinases; Mediating; Modeling; mouse model; Mus; novel; novel therapeutics; Parents; Pathway interactions; Patients; Peptide Receptor; Peptides; Phase; Physiology; Plasma; pre-clinical; Pregnancy; prevent; primary sclerosing cholangitis; Property; receptor; Recombinants; Recurrence; Relaxin; RXFP2 gene; Signal Transduction; Therapeutic; Time; Toxic effect; Variant; Vasodilator Agents; Work
