SBIR/STTR Award attributes
Activation of liver myofibroblastsLMFof different origins is responsible for the development of liver fibrosis in chronic liver diseases of all causes and remarkablyLMF clearance by apoptosis may prevent development of liver fibrosis and liver injuryand possibly allow recovery from reversal of liver fibrosisInhibiting o reversing myofibroblast activationthe therapeutic cellular targetis critical for the treatment of liver fibrosisBoth preventing progression of liver fibrosis as well as possiblyregression of liver fibrosis despite continued liver injuryas we documented in our pre clinical studiesare considered important clinical targets for patients with advanced liver fibrosis and cirrhosisFinallyblocking the progression of liver fibrosis would decrease development of primary liver cancer since most hepatocellular carcinomas arise in cirrhotic liversThe basis for our Research and Development is the development of a novelhumanizedtherapeutic peptideXFBWe created a library using analog synthesis to improve potential pitfalls for human therapyWe have performed in a step wise manner assays to select the safest and most efficienthumanizedpeptideincluding medicinal chemistrystability assays in human plasma and human liver microsomesapoptosis assays in activated primary human liver myofibroblastscell free caspaseactivation assaysliver injury fibrogenesis modelspharmacokineticsbioassayCYPinhibition studiesimmunogenicity assays in human T cells and in micecardiotoxicity assays in human stem cell derived cardiomyocytesand toxicology assays in HCV infected primary human hepatocytes and in normal and cirrhotic miceIn an animal model of decompensated cirrhosisthe XFBpeptide rescues hepatocyte cell death and liver failureand remarkably prevents byanimal mortality from weekto weekWe have developed a novelfirst in class inhibitor of a site specific phosphorylationand highly effective antifibrotic peptide in animal modelswith no evidences of immunogenicityand with exceptional stability in human microsomal systems and human plasmaXFBhas excellent solubility in waterThese features should facilitate administration by subcutaneous injection with excellent bioavailability during clinical trials judging by the steady state release in plasma of XFBfrom the PEG XFBThe PEG XFBwas not toxic to mice atfold the therapeutic doseThere was no evidence of cardiotoxicity or inhibition of CYPisoenzymesThe aims that are proposed for this SBIR are to complete IND enablingFDA mandated studiesThere is no FDA approved medication for the treatment of liver fibrosisand none of the drugs currently in Clinical Studies target directly activated myofibroblasts PROJECT NARRATIVE Chronic liver diseasesthrough inflammation and injury induce the development of scar tissue in the liverthis is called liver fibrosisThe medical and financial burden of liver diseases to the USA is substantialas it is associated with chronic hepatitis B and Cfatty liver of alcoholismobesity and diabetesand genetic disordersAdditional knowledge gained by with this work will facilitate the development of a medication for the treatment of liver fibrosis
