Combination therapy using siRNA nanocompelex and PD-L1 inhibitor for alcoholic liver fibrosis

siRNA纳米复合物与PD-L1抑制剂联合治疗酒精性肝纤维化

• 批准号: 10217954
• 负责人: Kun Cheng
• 金额: $ 34.94万
• 依托单位: UNIVERSITY OF MISSOURI KANSAS CITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10217954
• 关键词: Accounting; Adult; Affect; Alcohol abuse; Alcohols; Antibodies; Apoptosis; B-Lymphocytes; Binding; Biodistribution; Biotin; Blood Circulation; CD8-Positive T-Lymphocytes; Carbon Tetrachloride; Cells; Chemicals; Chronic; Cirrhosis; Clinical Research; Collagen; Collagen Type I; Combined Modality Therapy; Critical Pathways; Developed Countries; Dose; Ethanol; Event; Extracellular Matrix; Generations; Genes; Glycine; Goals; Half-Life; Hepatic Fibrogenesis; Hepatic Stellate Cell; Human; IGF2R gene; IL2RA gene; Immune; Immune response; Immunosuppression; In Vitro; Jurkat Cells; Left; Length; Libraries; Ligands; Ligation; Liver; Liver Cirrhosis; Liver Fibrosis; Mediating; Medicine; Messenger RNA; Modeling; Modification; Molecular Weight; Morbidity - disease rate; PD-1 blockade; PD-1/PD-L1; PDL1 inhibitors; PDL1 pathway; Pathway interactions; Peptide Nucleic Acids; Peptides; Polyethylene Glycols; Process; RNA-Binding Proteins; Rattus; Regulatory T-Lymphocyte; Role; Signal Pathway; Small Interfering RNA; Specificity; Surface; System; T cell response; T-Lymphocyte; Testing; Time; United States; Vertebral column; anti-PD-L1; anti-PD-L1 antibodies; base; bile duct; cytokine; design; effective therapy; experimental study; feeding; fibrogenesis; global health; gut microbiota; immune clearance; immunoregulation; improved; in vivo; microbiota; mortality; nanobodies; neutravidin; novel; overexpression; prevent; problem drinker; programmed cell death ligand 1; standard care; uptake; wound healing

Project Summary Liver fibrosis is a wound healing process characterized by the accumulation of excess extracellular matrix (ECM) in the liver. Alcohol abuse is one of the most common causes of liver fibrosis/cirrhosis in western developed countries, accounting for more than 50% of cirrhosis cases. If left untreated, liver fibrosis will develop into liver cirrhosis, which is irreversible and affects nearly 633,233 adults in the United States. Unfortunately, there is no standard treatment for liver fibrosis till now. Therefore, effective antifibrotic medicines are needed urgently The accumulation of type I collagen in fibrotic liver is primarily due to an increase in the half-life of its mRNA in activated hepatic stellate cells (HSCs). We recently demonstrated that blocking PCBP2 expression using siRNA can efficiently decrease the stability of the collagen α1(I) mRNA and subsequently reverse alcohol- and cytokine-induced fibrogenesis in HSCs. We also discovered an IGF2R-specific peptide that can be used to specifically deliver cargos to activated HSCs. We will improve our current nanocomplex system to enhance the delivery of the PCBP2 siRNA to activated HSCs. It has been well established that the activation and proliferation of HSCs is the central event in liver fibrogenesis. Recently, experimental and clinical studies have shown that inducing apoptosis of activated HSCs in fibrotic liver is a rational and potential anti-fibrotic approach. It was found that HSCs inhibit T cells and B cells through PD-L1 on the surface of HSCs. PD-L1 is overexpressed in activated HSCs, leading to the strong immune modulatory activity of the activated HSCs against T-cell response. Activated HSCs exert inhibitory effects on infiltrating CD8+ T cells and induction effects on CD4+CD25+ regulatory T (Treg) cells. The immune modulatory activity of activated HSCs can be reversed by anti- PD-L1 antibodies to block the PD-1/PD-L1 interaction. We therefore hypothesize that anti-PD-L1 inhibitor can be utilized to restore the activity of infiltrating T cells in the fibrotic liver to clear activated HSCs which overexpress PD-L1. Our strategy is to develop a combination therapy to reverse the accumulated type I collagen using PCBP2 siRNAs and induce apoptosis of activated HSCs using PD-L1 inhibitors. Our central hypothesis is that alcoholic liver fibrosis can be reversed by targeting two different key steps in liver fibrogenesis.

项目摘要 肝纤维化是一种伤口愈合过程，其特征是细胞外多余 肝脏中的基质（ECM）。酗酒是肝纤维化/肝硬化最常见的原因之一 西方发达国家占肝硬化病例的50％以上。如果未治疗，肝脏 纤维化将发展为肝硬化，这是不可逆的，影响了近633,233名成年人 美国。不幸的是，到目前为止，还没有针对肝纤维化的标准治疗方法。所以， 紧急需要有效的抗纤维化药物 I型胶原蛋白在纤维化肝脏中的积累主要是由于半衰期增加 它的激活肝星状细胞（HSC）中的mRNA。我们最近证明了阻止PCBP2 使用siRNA的表达可以有效地降低胶原蛋白α1（i）mRNA和 随后逆转HSC中的酒精和细胞因子诱导的纤维发生。我们还发现了一个 IGF2R特异性肽可用于专门为活化的HSC提供碳。我们将 改善我们当前的纳米复合系统，以增强PCBP2 siRNA的递送 HSC。 已经很好地确定，HSC的激活和增殖是肝脏中的中心事件 纤维发生。最近，实验和临床研究表明，诱导的凋亡 纤维化肝脏中活化的HSC是一种有理且潜在的抗纤维化方法。发现HSCS 通过HSC表面上的PD-L1抑制T细胞和B细胞。 PD-L1在激活中过表达 HSC，导致激活的HSC对T细胞反应的强烈免疫调节活性。 活化的HSC对浸润CD8+ T细胞产生抑制作用，并诱导对CD4+ CD25+的影响 调节t（Treg）细胞。激活的HSC的免疫调节活性可以通过抗 - PD-L1抗体阻断PD-1/PD-L1相互作用。因此，我们假设抗PD-L1 抑制剂可用于恢复纤维化肝脏中浸润T细胞的活性以清除活化 过表达PD-L1的HSC。 我们的策略是开发一种组合疗法，以扭转使用I型胶原蛋白的累积 PCBP2 siRNA并使用PD-L1抑制剂诱导活化的HSC凋亡。我们的中心假设 是否可以通过针对肝纤维发生的两个不同的关键步骤来逆转酒精性肝纤维化。