A Novel Treatment for Acetominophen-Induced Liver Injury

Abstract The Specific Aim of this Phase I STTR proposal is to test the feasibility of blocking MCJalso called DnaJCto overcome acute acetaminophen liver toxicityAcetaminophen or APAPfrom acetyl paraaminophenolis a common drug used to address pain and feverIn the US aloneaboutpatients per year are admitted to intensive care units with APAP induced liver injury and close toof these patients undergo liver transplantationFor overdosingtreatment with the antioxidant N acetylcysteineNACis the only known effective approachNAC is very effective at reducing APAP induced liver injury if given withinhours after ingestionHoweverafter abouthoursNAC has a minimal chance of rescuing the livertherefore alternative therapeutic approaches are neededWhile the mechanisms underlying APAP induced acute liver injury are not fully understoodincreased oxidative stress and reduction in ATP production due to the effect of APAP on mitochondrial electron transport chainETCseem to play a major role in hepatocyte cell deathThusincreasing mitochondrial respiration without increasing oxidative stress could be a potential therapeutic approach to address APAP liver toxicityHoweverthis approach has not been previously tested because there are no available strategies to enhance mitochondrial respirationMCJ is an endogenous negative regulator of Complex Ia key component of the mitochondrial respiratory chainThe absence of MCJ has been shown to enhance mitochondrial ATP productionwithout increasing production of reactive oxygen speciesROSThusreducing MCJ could be an approach to protect mitochondria in liver from APAP induced liver injuryUnder physiological conditionscomplete removal of MCJ has no obvious toxic effectsThuswe predicted that blocking MCJ expression could be a relatively safe approach to protect from APAP induced liver injuryIn factwe have found that siMCJ treatment shows a superior efficacy to NAC in treating APAP induced liver injury in a mouse modelWe have demonstrated highly effective therapeutic efficacyeven when administeredhours after APAP administrationTo achieve our Specific Aimwe will carry outTasksTaskEstablish the maximum tolerated doseMTDor a high tolerated dose of siMCJTaskTo establish a dose effect of siMCJ on APAP induced liver injuryTaskTo establish the effect of siMCJ treatment on long term recovery from APAP induced liver injuryTaskTo validate that the therapeutic effect of siMCJ is maintained in the presence of NACthe current standard of care treatment for APAP induced liver injuryTest of FeasibilityThe therapeutic indexTIi eMTD ECmust be andgtand long termweekrecovery must be complete enough to prevent the need to sacrifice miceMaximal efficacy must be maintained when siMCJ is co delivered with NAC Narrative Acetaminophen overdose is the major cause of liver failure in the USThere is no current treatment to prevent this liver failureThis is a proposal to develop a safe and affordable treatment that will prevent liver failure in patients at risk of acetaminophen induced liver failure