Treatment of alcoholic liver disease with novel targeted inhibitors

DESCRIPTION provided by applicant Alcoholic liver disease ALD affects millions of people globally and often leads to fibrosis and cirrhosis With a total of deaths in of which were alcohol related liver cirrhosis is the th leading cause of death in the United States and costs society more than $ 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 an inflammation amplifier is involved in a variety of inflammation associated diseases Blockade of TREM attenuates inflammation and improves outcome in mice with sepsis cancer rheumatoid arthritis and other inflammatory disorders Recently deficiency of TREM 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 can be used to prevent and treat ALD This is rationalized by the fact that TREM is upregulated under inflammatory conditions and induces proinflammatory cytokines expression Current approaches to TREM suggest to block binding of ligand to TREM The true nature of the TREM 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 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 targeted approach to prevention and treatment of ALD Phase I specific aims are to test TREM inhibitors in Kupffer cells alone and co cultured with hepatocytes and test TREM 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 SignaBlokandapos s proprietary nanosystem for macrophage specific delivery We will synthesize nanoformulations that contain TREM 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 PUBLIC HEALTH RELEVANCE Alcoholic liver disease ALD affects over million people worldwide with more than 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