Alcoholic liver disease (ALD) affects millions of people globally and often leads to fibrosis and cirrhosis. With a total of 29,925 deaths in 2007, 48% of which were alcohol related, liver cirrhosis is the 12th leading cause of death in the United States and costs society more than $15 billion annually. Despite this tremendous societal and economic burden, no approved therapeutics for ALD are available. Current treatments include corticosteroids, immunosuppressants, and antioxidants. They all have multiple shortcomings including a high level of serious side effects and insufficient efficacy. This highlights the need for new, liver-specific treatments. Alcohol-mediated activation of Kupffer cells, resident macrophages of the liver, results in proinflammatory cytokine production and ultimately, liver damage. This suggests Kupffer cell activation as a promising target for prevention and treatment of ALD. Triggering receptor expressed on myeloid cells (TREM-1), an inflammation amplifier, is involved in a variety of inflammation-associated diseases. Blockade of TREM-1 attenuates inflammation and improves outcome in mice with sepsis, cancer, rheumatoid arthritis and other inflammatory disorders. Recently, deficiency of TREM-1 expressed by Kupffer cells has been shown to attenuate Kupffer cell activation, resulting in diminished chemically induced liver injury. We hypothesize that inhibition of TREM-1 can be used to prevent and treat ALD. This is rationalized by the fact that TREM-1 is upregulated under inflammatory conditions and induces proinflammatory cytokines expression. Current approaches to TREM-1 suggest to block binding of ligand to TREM-1. The true nature of the TREM-1 ligand is not yet known, highly increasing the risk of failure of these approaches in clinical development. Recently, we demonstrated in animal models that a novel peptide inhibitor of TREM-1 suppresses inflammatory response and ameliorates cancer and sepsis. The peptide employs a ligand-independent mechanism of action and is non-toxic. The long-term objective of the proposed project is to develop a novel, TREM-1-targeted approach to prevention and treatment of ALD. Phase I specific aims are to: 1) test TREM-1 inhibitors in Kupffer cells alone and co-cultured with hepatocytes, and 2) test TREM-1 inhibitors in a mouse model of alcoholic liver disease. In order to increase peptide solubility, bioavailability and targeting to sites of inflammation, we will utilize SignaBlok's proprietary nanosystem for macrophage-specific delivery. We will synthesize nanoformulations that contain TREM-1 inhibitory peptide and assess their inhibitory activity in vitro using rat Kupffer cells cultured alone or co- cultured wih rat hepatocytes. We will vary the composition of nanoparticles and choose the optimal formulation based upon peptide content and inhibitory activity. In order to assess therapeutic efficacy of the optimal formulation in vivo, we will use a mouse model of ALD. In order to evaluate liver damage, we will measure serum alanine aminotransferase in the serum and perform thorough histopathological analysis of the liver sections. We will also analyze proinflammatory cytokines in the serum and in the liver. It is anticipated that the Phase I study will identify novel, first-in-class targeted agents that will provide a powerful platform for prevention and treatment of ALD. If successful, the Phase I will be followed in the Phase II by toxicology, absorption/disposition/metabolism/excretion (ADME), pharmacology and chemistry/ manufacturing/ control (CMC) studies, filing an Investigational New Drug (IND) application with the US Food and Drug Administration (FDA) and subsequent evaluation in humans. Importantly, the macrophage- specific nanoparticles is a versatile multifunctional delivery platform. Thus, successful completion of Phase I will provide the proof of concept of the hypothesis that might be applicable for a targeted combination therapy of ALD.
Alcoholic liver disease (ALD) affects over 140 million people worldwide with more than 12,000 deaths per year attributed to ALD in the United States. Currently, there is no specific medical treatment for ALD. The proposed research will result in the development of novel mechanism-based agents that could substantially improve prevention and treatment of ALD, allowing for reduction of alcohol-related morbidity and mortality.
