Advancing the Treatment of Alcohol Associated Liver Disease by Precision Targeting Methyltransferase-like Protein family

About This Grant

Project Summary/Abstract Alcohol-associated liver disease (ALD) progresses from fatty liver to severe stages like alcoholic steatohepatitis, fibrosis, and cirrhosis. Despite its common occurrence and significant health impact, there are no approved drugs for ALD. Our primary objective is to uncover therapeutic targets and develop effective treatments for ALD. Fatty liver in ALD is characterized by the accumulation of lipid droplets (LDs) and is closely associated with genetic variant mutations including PNPLA3-I148M variant. Our research focuses on a group of human enzymes called methyltransferase-like (METTL) proteins, notably METTL7A, is highly expressed in healthy human livers and significantly upregulated in ALD patients, particularly phosphorylated at serine 53 (hMETTL7A-S53). This elevation significantly correlates with the severity of steatosis, inflammation, and fibrosis. Furthermore, our analysis suggests an interaction between hMETTL7A-S53 and PNPLA3-I148M variant. Knockdown of hMETTL7A or inactivation of hMETTL7A-S53 reduces ethanol-induced lipid accumulation and PNPLA3 levels, supporting its role as a precision therapeutic target for ALD. We hypothesize that targeting hMETTL7A-S53 and its association with PNPLA3-I148M is an effective approach for ALD treatment. Our approaches utilize cutting- edge technology and human hepatocytes to study the protein interactions, and FDA-approved liver-specific RNAi and AAV-based gene delivery. We will assess the effectiveness of two formulations to treat ALD including GalNAc-siRNA-METTL7A conjugates to inhibit hMETTL7A, and AAV7-hMETTL7A-S53A (Serine 53 is replaced by Alanine) to deactivate hMETTL7A phosphorylation. Aim 1 Determine the mechanism of hMETTL7A interaction and stabilization of PNPLA3-I148M and evaluate the manipulation of this interaction for therapeutic benefits in ALD. Aim 2 Test the therapeutic efficacy of the two formulations in both the prevention and reversal of ALD. The goal of this project is to establish hMETTL7A as a promising therapeutic target for the precise treatment of ALD, particularly in cases associated with PNPLA3-I148M variant. This initiative represents an innovative investigation into METTL proteins, with the aim to leverage their potential for advancing clinical interventions in ALD treatment.