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A Novel Treatment for Acetominophen-Induced Liver Injury

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41DK117760-01A1
Agency Tracking Number: R41DK117760
Amount: $264,238.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: 300
Solicitation Number: PA17-303
Timeline
Solicitation Year: 2017
Award Year: 2018
Award Start Date (Proposal Award Date): 2018-07-01
Award End Date (Contract End Date): 2019-06-30
Small Business Information
22 ALYSSA DR
Cheshire, CT 06410-7118
United States
DUNS: 079732386
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 MERCEDES RINCON
 (802) 863-9663
 mrincon@uvm.edu
Business Contact
 ROBERT HEMLEY
Phone: (203) 240-9566
Email: rhh134@comcast.net
Research Institution
 UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
 
85 SOUTH PROSPECT STREET
BURLINGTON, VT 05405-1704
United States

 Nonprofit college or university
Abstract

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

* Information listed above is at the time of submission. *

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