Targeting galectin-3 for treatment of NASH mediated fibrosis

Project Summary Abstract Non alcoholic steatohepatitisNASHand resultant liver fibrosis is a major health problem in the United States and the rest of the worldCurrentlythere are no FDA approved medical therapies for NASH mediated liver fibrosisand so effective antifibrotic drugs that reverse the disease are urgently neededCompelling evidence suggests that galectinGala beta galactoside binding lectincontributes to fibrogenesis in various organs including liver as inhibition of Galwith carbohydrate ligands or knock down of Galattenuated fibrosisOverallresults suggest that specific inhibition of Galmay represent a promising therapeutic strategy against tissue fibrosisIn Galectin Therapeuticsrecent phase IIb clinical trial on NASH fibrosis and cirrhosis patientsGR MDa known Galantagonist derived from modified citrus pectinMCPfailed to achieve statistically significant data in reducing hepatic venous pressure gradientHVPGprimary endpointwhen the total group of patients was consideredhttpsseekingalpha com articlegalectin therapeutics lackluster trialresults bad credit line somehow jump stockpercentHowevera statistically significant result of GR MDwas observed only in the subgroup of NASH cirrhosis patients without esophageal varicesThe failure of GR MDto treat NASH fibrosis could be attributed to its non specificity and low affinityMto GalButGals natural affinity to its intrinsic carbohydrate ligands is in the nano molar rangeThe trial result also suggests that high affinity drug that can specifically target Galin NASH fibrosis patients is yet to be discoveredOur scientific premise is that we have developed a very potent Galantagonistnamed TFDfrom a natural dietary sourcePNASPMIDTFDbinds specificallyon targetto Galwith picomolar affinitythe affinity is so highfold moreto outcompete Gals natural affinity to its intrinsic ligandsIn our preliminary studiesTFDreduces Galmediated pro inflammatory factors and shows beneficial effect over MCPOur research team has extensive expertise in two relevant mouse models of human Nonalcoholic steatohepatitisNASHand liver fibrosisHigh fat dietHFDmodel in CBLmiceStreptozotocin injury followed by insult with HFDandCarbon tetrachlorideCClmodel in CBLmiceWe have shown that galectinexpression isfold higherpandltin liver of the former mouse model at the onset of fibrosisBased on the compelling preliminary data we hypothesize that the specific inhibition of Galwith TFDwill suppress NASH mediated liver fibrosis by impeding pro fibrotic factorsTo test this hypothesiswe will first determine TFDs maximum tolerated doseMTDin CBLmiceWe will then in vivo determine TFDs ability to treat NASH mediated liver fibrosis in our two mouse modelsAfter drug treatmentliver tissue will be examined for histopathology evaluationincluding deposition of collagenprimary endpointhepatocellular fat accumulationhepatocyte ballooningintra portal and intra lobular inflammatory infiltrateWe will also determine changes in pro fibrotic factors and cell fate after TFDadministration in vivoParticularlywe will measure the levels of cytokines and other genes such as TGFbILscollagensGaland extracellular matrix proteinsWe will determine differential expression of liver markers and proinflammatory fibrotic immune cell frequenciesThis studyfor the first timewill explore the therapeutic utility of a very potent natural carbohydrate compound that outcompetes Gals natural affinity to treat NASH mediated fibrosis Project Narrative Galectinpromotes profibrotic factors in nonalcoholic steatohepatitisNASHmediated liver fibrosisWe will use a natural high affinity galectinblocker to treat NASH mediated liver fibrosis