AH (AH) is a major cause of morbidity and mortality due to a lack of effective treatments for this condition. As stated in RFA-AA-12-007, translational investigations are needed on new mechanisms and suitable pharmacological agents relevant to AH. This application is one of three that comprise a consortium (Translational Research and Evolving Alcoholic Hepatitis Treatment;TREAT) and include Indiana University, Virginia Commonwealth University, and Mayo Clinic. The Overall goals of the TREAT consortium are to perform patient oriented translational studies that will uncover and test new pharmacologically relevant targets for the treatment of AH. This specific TREAT-Mayo application will focus on expansion of recent studies that have revealed a key role for caspase dependent cell death pathways as a pathogenic culprit in AH. In this proposal, we will test the Central Hypothesis that the novel caspase inhibitor emricasan is safe and effective in patients with AH through a mechanism involving inhibition of hepatocellular apoptosis and sterile necrosis. We will also support the broader goals of the TREAT consortium by recruiting patients for a well annotated registry and by providing a mechanistic resource for human serum and liver tissue analyses that are broadly pertinent to liver injury, inflammation, and cell death. Thus, the Specific Aims of thi application are to: 1) Develop longitudinal observational cohort of patients with AH. We will develop a prospective multicenter registry of patients with well characterized AH and suitable controls that serves as the clinical and biosample based foundation for conducting human therapeutic (as described in Aim 2) and novel mechanistic (as described in Aim 3) studies. 2) Test the hypothesis that 4-week emricasan administration will improve survival in patients with AH. We will conduct an early phase randomized, blinded, placebo controlled study, which will include a special population of patients with severe AH who are not otherwise candidates for corticosteroid therapy based on specific contraindications. 3) Test the hypothesis that apoptosis and sterile necrosis contribute to development of AH and are pathogenic targets of emricasan. We will measure serum and liver tissue markers of both apoptosis and sterile necrosis to inform our understanding of how these molecular processes contribute to liver injury and inflammation in human AH. Thus, this study, submitted by a group of investigators with extensive experience in clinical AH and basic liver injury, will determine the safety and potential efficacy of a novel and innovative therapy, the caspase inhibitor emricasan, in patients with AH. Additionally, the proposed mechanistic analyses will elucidate how distinct cell death pathways contribute to human AH and how caspase inhibition abrogates these pathways thereby inhibiting liver injury and inflammation in patients with AH. Our track record in patient recruitment trials and expansive resources in liver injury pathways will also provide key components for the broader success of this consortium. In total, this application will provide a major step in advancing our understanding of the devastating condition of AH.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project--Cooperative Agreements (U01)
Project #
3U01AA021788-02S1
Application #
8706608
Study Section
Program Officer
Orosz, Andras
Project Start
2013-08-01
Project End
2017-06-30
Budget Start
2013-09-05
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$34,999
Indirect Cost
$12,987
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Samala, Niharika; Lourens, Spencer G; Shah, Vijay H et al. (2018) Posttraumatic Stress Disorder in Patients with Heavy Alcohol Consumption and Alcoholic Hepatitis. Alcohol Clin Exp Res 42:1933-1938
Liangpunsakul, Suthat; Beaudoin, James J; Shah, Vijay H et al. (2018) Interaction between the patatin-like phospholipase domain-containing protein 3 genotype and coffee drinking and the risk for acute alcoholic hepatitis. Hepatol Commun 2:29-34
Peeraphatdit, Thoetchai Bee; Simonetto, Douglas A; Shah, Vijay H (2018) Exploring new treatment paradigms for alcoholic hepatitis by extrapolating from NASH and cholestasis. J Hepatol 69:275-277
Singal, Ashwani K; Louvet, Alexandre; Shah, Vijay H et al. (2018) Grand Rounds: Alcoholic Hepatitis. J Hepatol 69:534-543
Chirapongsathorn, Sakkarin; Krittanawong, Chayakrit; Enders, Felicity T et al. (2018) Incidence and cost analysis of hospital admission and 30-day readmission among patients with cirrhosis. Hepatol Commun 2:188-198
Puri, Puneet; Liangpunsakul, Suthat; Christensen, Jeffrey E et al. (2018) The circulating microbiome signature and inferred functional metagenomics in alcoholic hepatitis. Hepatology 67:1284-1302
Greuter, Thomas; Shah, Vijay H (2018) Too Stiff, Too Late . . . Timing Is Everything in Antiangiogenic Treatment of Liver Fibrosis. Hepatology :
Greuter, Thomas; Malhi, Harmeet; Gores, Gregory J et al. (2017) Therapeutic opportunities for alcoholic steatohepatitis and nonalcoholic steatohepatitis: exploiting similarities and differences in pathogenesis. JCI Insight 2:
Lourens, Spencer; Sunjaya, Dharma B; Singal, Ashwani et al. (2017) Acute Alcoholic Hepatitis: Natural History and Predictors of Mortality Using a Multicenter Prospective Study. Mayo Clin Proc Innov Qual Outcomes 1:37-48
Mauer, Amy S; Hirsova, Petra; Maiers, Jessica L et al. (2017) Inhibition of sphingosine 1-phosphate signaling ameliorates murine nonalcoholic steatohepatitis. Am J Physiol Gastrointest Liver Physiol 312:G300-G313

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