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Treatment of advanced liver fibrosis in HIV- and HCV-infected adults with simtuzumab, a monoclonal antibody against lysyl oxidase-like 2: Results of a 6-month open-label safety trial

ABSTRACT: Chronic liver injury can result in fibrosis that may progress over years to end-stage liver disease. The most effective antifibrotic therapy is treatment of the underlying disease, however when this is not possible, interventions to reverse fibrosis are needed. We conducted an open-label pilot trial to study the safety and tolerability of simtuzumab, a monoclonal antibody directed against lysyl oxidase-like 2 (LOXL2) enzyme, in patients with advanced liver disease from hepatitis C virus (HCV), human immunodeficiency virus (HIV), or HCV-HIV co-infection. 18 patients with advanced liver fibrosis received simtuzumab 700mg IV every 2 weeks for 22 weeks. There were no discontinuations due to adverse events. No significant change was seen in hepatic venous pressure gradient or liver biopsy fibrosis score after treatment. Exploratory transcriptional and protein profiling using paired pre- and post-treatment liver biopsies, serum, and whole blood identified upregulation of TGFβ3 and IL-10 pathways with treatment. In summary, simtuzumab was well tolerated in HCV- and HIV-infected patients with advanced liver disease. Modulation of TGFβ3 and IL-10 pathways as a result of simtuzumab treatment merits investigation in future trials.

ORGANISM(S): Homo sapiens

PROVIDER: GSE73634 | GEO | 2017/09/08

SECONDARY ACCESSION(S): PRJNA297462

REPOSITORIES: GEO

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Project description:End stage liver disease due to Hepatitis C Virus (HCV) infection is a major health concern worldwide. Liver fibrosis following chronic HCV infection plays a pivotal role in loss of liver function and end stage liver disease. However the dynamics and molecular events that lead to fibrosis in HCV infection are poorly defined. Therefore, we determined the influence of HCV infection in altering the miRNA expression levels which can modulate immune responses to HCV leading to fibrosis. Analysis of the miRNA expression profiles of HCV infected liver biopsies revealed that 45 miRNAs were differentially expressed in the HCV infected liver when compared to normal livers. In silico target prediction of these differentially expressed miRNAs indicated that their targets include chemokine/cytokine signaling, cell cycle genes and extracellular matrix protein gene expression. Gene expression profiling using whole genome microarray demonstrated that 1320 genes were differentially expressed in chronic HCV liver when compared to normal. These genes could be functionally grouped into those involved in cell cycle regulation, cytokines and chemokines expression, cell adhesion, intracellular signaling and enzymes. Further pathway analysis using GeneGo software identified cell adhesion, cytoskeleton remodeling, cytokine signaling and metabolic pathways as the major pathways activated in chronic HCV. Combinatorial target prediction analysis of miRNA expression along with gene expression analysis indicated that differentially expressed microRNAs in HCV significantly impact transforming growth factor beta (TGF-?) signaling pathway, cell adhesion (integrin expression), chemokine signaling, Notch signaling and cell-cycle( Cyclin D,K) regulation. Overall these results demonstrate that chronic HCV infection induces specific miRNA signatures that will modulate genes involved in the cytoskeletal remodeling and cytokine signaling that can promote the development of fibrosis following HCV infection. Liver biopsies from chronic HCV patients and control liver biopsies from normal subjects (donor liver prior to transplantation) were used to analyze the miRNA and gene expression profile. Patients with HBV and/or HIV were excluded from the study. This Series represents the mRNA gene expression profiling data only.

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Treatment of advanced liver fibrosis in HIV- and HCV-infected adults with simtuzumab, a monoclonal antibody against lysyl oxidase-like 2: Results of a 6-month open-label safety trial

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