Activation of hepatic stellate cells (HSC) is responsible for the development of liver fibrosis in chronic liver diseases of all causes and remarkably, HSC clearance by apoptosis may allow recovery from liver injury and reversal of liver fibrosis. There is full agreement among liver fibrosis experts that inhibiting o reversing HS activation (the therapeutic target) is critical for the treatment of liver fibrosis. Both regressio of liver fibrosis as well as lack of progression of liver fibrosis, in spite of continued liver injury as we clearly documented in our pre-clinical studies, are considered important clinical targets for patients with chronic liver disease and liver fibrosis. Finally, blocking the progression of liver fibrosis would decrease development of primary liver cancer in these patients since the majority of hepatocellular carcinomas arise in cirrhotic livers. The basis for our Research and Development of the Ac-KAVD-CHO related peptoids are the following: i] that the nonphosphorylatable C/EBP¿-Ala217 transgene prevents phosphorylation of endogenous C/EBP¿, and activates caspase 8 resulting in apoptosis of HSC upon their activation, preventing progression and inducing regression liver fibrosis; ii] that neither the transactivation nor the leucine zipper domains are required for these effects; and iii] that a cell permeant tetrapeptide containing the RSK phosphoacceptor domain of C/EBP¿ is sufficient to replicate these effects . We created a library using analog synthesis to improve potential pitfalls for human use; ii] use in a step-wise manner assays to select the safest and most efficient peptides (including apoptosis assays in activated primary human HSC; cell-free caspase 8 activation assays; acute liver injury/fibrogenesis models; toxicology assays in highly differentiated, primary human hepatocyte cultures and mice). We have developed effective antifibrotic compounds with expected decreased immunogenicity and improved stability and bioavailability during clinical trials. The proposed compounds markedly inhibit activation of human and mouse hepatic stellate cells in culture and in vivo in preclinical models of liver fibrosis and decreased liver injury. These compounds were not toxic in the preliminary toxicology studies, including toxicogenomics, to highly differentiated hepatocytes and mice at least at 100-fold the therapeutic dose. The aims that are proposed for completion by this STTR are: Chronic liver fibrogenesis assays in mouse models; Pharmacokinetics; In Vitro ADMET Studies :Metabolic stability; CYP-450 Inhibition; and Exploratory Toxicology; Dose Escalation Study and Repeat-Dose Range-finding Toxicity Study. There is no medication for the treatment or prevention of liver fibrosis. Completion of these tasks for the proposed compounds will allow us proceeding with a Phase-2 STTR and clinical development in patients with liver fibrosis.
Public Health Relevance Statement: Public Health Relevance: Chronic liver diseases, through inflammation and injury induce the development of scar tissue in the liver; this is called liver fibrosis. Excessive liver fibrosis can result in liver cirrhosis, which accounts for the significant complications and mortalty among the population with chronic liver diseases. The medical and financial burden of cirrhosis to the USA is substantial, as it is associated with Hepatitis B and C, fatty liver of obesity and diabetes and alcoholism. Additional knowledge gained by Xfibra with this work will facilitate the development of medication for the treatment of liver fibrosis. Development of effective treatments for liver fibrosis may also facilitate future treatments for lung and kidney fibrosis.
NIH Spending Category: Cancer; Chronic Liver Disease and Cirrhosis; Digestive Diseases; Liver Cancer; Liver Disease; Orphan Drug; Rare Diseases
Project Terms: Accounting; Acute; Agreement; Alcoholism; analog; Animals; Apoptosis; Area; Autopsy; base; Biological Assay; Biological Availability; Body Weight decreased; caspase-8; CCAAT-Enhancer-Binding Proteins; Cells; Chronic; chronic liver disease; Cicatrix; Cirrhosis; Clinical; Clinical Trials; Collagen; Development; Diabetes Mellitus; Dose; Drug Kinetics; Drug or chemical Tissue Distribution; effective therapy; Excretory function; Fatty Liver; fibrogenesis; Fibrosis; Future; Hepatic Fibrogenesis; Hepatic Stellate Cell; Hepatitis B; Hepatitis C; Hepatocyte; Histology; Human; immunogenicity; improved; In Vitro; in vivo; Inflammation; Injury; Kidney; Knowledge; Laser Microscopy; Lead; Leucine Zippers; Libraries; liquid chromatography mass spectrometry; Liver; Liver Cirrhosis; Liver Fibrosis; liver injury; Lung; Malignant neoplasm of liver; Mass Spectrum Analysis; Maximum Tolerated Dose; Medical; Messenger RNA; Metabolic; metabolic abnormality assessment; Modeling; Morbidity - disease rate; Mortality Vital Statistics; mouse model; Mus; Obesity; Oral Administration; Patients; Penetration; Peptides; Peptoids; Pharmaceutical Preparations; Phase; Phosphorylation; Plasma; Population; Pre-Clinical Model; preclinical study; prevent; Prevention; Primary carcinoma of the liver cells; Procedures; public health relevance; Recovery; Research; research and development; RNA; Sampling; Schedule; Serum; sex; Small Business Technology Transfer Research; Testing; Therapeutic; Therapeutic Agents; therapeutic target; Thioacetamide; Time; Tissues; Toxic effect; Toxicogenomics; Toxicokinetics; Toxicology; Trans-Activation (Genetics); Transgenes; urinary; Wo
