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A novel approach to treat non alcoholic steatohepatitis NASH

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41DK112429-01A1
Agency Tracking Number: R41DK112429
Amount: $317,953.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: 300
Solicitation Number: PA16-303
Timeline
Solicitation Year: 2016
Award Year: 2017
Award Start Date (Proposal Award Date): 2017-07-05
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) 656-0937
 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 treating non alcohol steatohepatitis
NASH by increasing mitochondrial metabolism which is the main pathway for lipid catabolism in the liver
NASH is a stage of non alcohol fatty liver disease NAFLD that has progressed to a pathological state NASH
can lead to cirrhosis leading to liver failure or hepatocellular carcinoma NASH is especially common in those
with other metabolic disorders such as obesity diabetes and or hyperlipidemia but also affects the healthy
population About of the population in US has NAFLD with million instances of NASH diagnosed each
year in the US with advanced fibrosis and about million individuals progressed to cirrhosis The primary
treatment for NASH is lifestyle change However few patients remain adherent for extended periods of time
No drugs have been approved by the FDA for treating NASH To address this need we are developing an
siRNA based drug to treat NASH by increasing liver metabolism Fatty acids are transported to the liver where
they are metabolized through beta oxidation coupled to the electron transport chain ETC in the mitochondria
Increased mitochondrial respiratory activity in the liver could therefore speed up the degradation of fatty acids
and prevent their accumulation in the liver A key regulator of the ECT is the MCJ protein MCJ DnaJC or
Methylation Controlled J protein MCJ is a mitochondrial protein that reduces respiration dependent ATP
levels We have demonstrated that removal of MCJ activity is safe and results in increased mitochondrial
metabolism ATP production We have developed an siRNA formulation siMCJ that effectively removes
mouse MCJ in the liver Using this formulation we have shown in two mouse models that we can reverse or
prevent NASH pathologies siRNA has been validated as a drug for number of diseases including liver
diseases with over clinical trials having been run thus validating the use of this therapeutic approach
While our preliminary data are compelling thus far the studies were carried out at only one dose of siRNA and
against the mouse MCJ protein Thus to show feasibility of our approach prior to carrying out IND enabling
studies we must carry out a more robust feasibility study that includes demonstration of safety a dose effect
relationship and efficacy of human siMCJ To this end we will carry out the following Tasks
Task Evaluate efficacy and toxicity of mouse siMCJ in vivo using mouse models
Task Evaluate efficacy human siMCJ in vivo using humanized liver mouse model KMT Mice
Test of Feasibility We must observe findings in Task that are similar to those in the preliminary study
section and we must observe a dose effect curve that can be fit to a standard Hill type or log logit analysis and
that covers the EC point of the curve We must observe a TI therapeutic index of at least maximally
effective dose MTD This TI would indicate a very safe dosing window since we use a maximally effective
dose as the numerator Findings in Task must also be similar to the findings in the preliminary study section Narrative
Non alcohol steatohepatitis NASH is a devastating disease for which there is no FDA approved treatment
NASH is an advanced stage of non alcoholic fatty liver disease NAFLD that can lead to cirrhosis liver failure
as well as hepatocellular carcinoma While the frequency of NASH is very high in those with other metabolic
disorders such as obesity diabetes and or hyperlipidemia about of healthy population also
has developed the first stage of the disease About million instances of NASH are diagnosed each year in the
US with advanced fibrosis and about million individuals have progressed to cirrhosis This is a proposal to
develop the first FDA approved treatment for NASH

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

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