Relaxin receptor agonists for treatment of liver fibrosis Grant

abstract

  • Fibrosis is an underlying cause of cirrhosis and hepatic failure resulting in end stage liver disease. There arecurrently no pharmacological treatments for advanced liver fibrosis. The abnormal proliferation and differentiationof mesenchymal stellate cells into myofibroblasts is the driving force of liver scaring, collagen accumulation, andextracellular matrix remodeling often associated with the increase of portal hypertension. In the last few yearsthe beneficial effects of relaxin peptide treatment have been demonstrated in clinically relevant animal modelsof liver disease. It has been shown that relaxin suppresses the activation of quiescent hepatic stellate cells andtheir differentiation into collagen producing myofibroblasts. Additionally, treatment with relaxin caused asignificant reduction of portal pressure in rats with induced liver fibrosis. Despite such favorable indications theuse of relaxin is complicated due to its short half-life in vivo thus requiring continuous peptide delivery; a potentialimmune response to the injected peptide; and the high cost of the recombinant peptide. Relaxin signals throughits cognate G protein-coupled receptor RXFP1 which is expressed in hepatic stellate cells. We have recentlyidentified a first series of small molecule agonists of RXFP1. These molecules are highly specific potentactivators of RXFP1; they have a long in vitro and in vivo half-life, a preferred ADME profile, and low cytotoxicity.The preliminary data suggest that the small molecule suppressed the expression of pro-fibrotic genes in primaryhuman stellate cells while increasing expression of genes participating in extracellular matrix degradation. Thecurrent application is designed to validate the therapeutic anti-fibrotic effects of RXFP1 agonists using unique invitro and in vivo models of liver fibrosis. First, we will test the efficacy of lead compounds to suppress fibrosis inactivated human stellate cells and test their effects on various liver cells. The selected compounds will be testedin liver mini-organoids, the complex fully functional mini-organs produced for high-throughput analysis oftherapeutic drug targets at the Wake Forest Institute for Regenerative Medicine. The most efficacious agonistwith low cytotoxicity and no effects on normal hepatic cell function will be selected for animal testing. As RXFP1agonists do not activate rodent receptors we have produced an RXFP1 humanized strain of mice with theendogenous mouse relaxin receptor replaced by a fully functional human receptor. Using this model we will testthe anti-fibrotic properties of relaxin agonists in a toxic chemical liver CCl4 insult model and in a cholestatic liverinjury model. These two models reflect different ontogeny and localization of liver fibrosis in humans. The resultsof our experiments will provide a foundation for future translational studies of relaxin receptor agonists for treatingfibrosis in liver and other organs.

date/time interval

  • March 1, 2017 - February 28, 2022

sponsor award ID

  • 1R01DK110167-01A1

local award ID

  • AWD000000006952

contributor

keywords

  • Agonist
  • Alcoholic Liver Diseases
  • Animal Feed
  • Animal Model
  • Animal Testing
  • Animals
  • Biochemical
  • Biological Assay
  • Biology
  • Cell Survival
  • Cell physiology
  • Chronic
  • Chronic Hepatitis C
  • Cicatrix
  • Cirrhosis
  • Clinical Research
  • Collagen
  • Complex
  • Data
  • Development
  • Disease
  • Drug Targeting
  • Evaluation
  • Extracellular Matrix
  • Extracellular Matrix Degradation
  • Fibrosis
  • Foundations
  • Future
  • G-Protein-Coupled Receptors
  • Gene Expression
  • Genes
  • Goals
  • Growth
  • Half-Life
  • Healthcare Systems
  • Hepatic Stellate Cell
  • Hepatocyte
  • Human
  • Immune response
  • In Vitro
  • Infection
  • Inflammation
  • Injectable
  • Injection of therapeutic agent
  • Institutes
  • Lead
  • Liver
  • Liver Failure
  • Liver Fibrosis
  • Liver diseases
  • Mesenchymal Differentiation
  • Modeling
  • Molecular
  • Mouse Strains
  • Mus
  • Myofibroblast
  • Organ
  • Organoids
  • Orthologous Gene
  • Peptides
  • Pharmaceutical Preparations
  • Pharmacological Treatment
  • Pharmacology
  • Pharmacotherapy
  • Phenotype
  • Play
  • Poisons
  • Portal Hypertension
  • Portal Pressure
  • Process
  • Production
  • Property
  • Proteins
  • RNA
  • Rattus
  • Recovery
  • Regenerative Medicine
  • Relaxin
  • Rodent
  • Role
  • Route
  • Series
  • Signal Transduction
  • Source
  • System
  • Testing
  • Therapeutic
  • Therapeutic Agents
  • Therapeutic Effect
  • Toxic effect
  • cell type
  • clinically relevant
  • cost
  • cytotoxicity
  • design
  • dosage
  • driving force
  • efficacy testing
  • experimental study
  • forest
  • high throughput analysis
  • human disease
  • in vivo
  • in vivo Model
  • interest
  • knockout animal
  • liver function
  • liver injury
  • liver transplantation
  • nonalcoholic steatohepatitis
  • pre-clinical
  • receptor
  • recombinant peptide
  • relaxin receptor
  • response
  • screening
  • small molecule
  • stellate cell
  • tissue regeneration
  • translational study