Evaluation of anti-fibrotic and anti-inflammatory semi-synthetic oxysterol, Oxy210, as a therapeutic drug candidate for non-alcoholic steatohepatitis

抗纤维化和抗炎半合成氧甾醇 Oxy210 作为非酒精性脂肪性肝炎候选治疗药物的评价

• 批准号: 10697132
• 负责人: FARHAD PARHAMI
• 金额: $ 89.7万
• 依托单位: MAX BIOPHARMA, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10697132
• 关键词: Actins; Acute; Affect; Agonist; Alcoholic Fatty Liver; Anti-Inflammatory Agents; Antiinflammatory Effect; Apoptosis; Atherosclerosis; Award; CETP gene; COL1A1 gene; California; Cardiovascular Diseases; Cells; Cholesterol; Chronic; Circulation; Cirrhosis; Collagen; Deposition; Development; Diabetes Mellitus; Diet; Disease; Drug Kinetics; Endocrinology; Endogenous Factors; Erinaceidae; Esterification; Evaluation; Exposure to; FDA approved; Family; Fatty acid glycerol esters; Fibrosis; Future; Gene Expression; Genotype; Grant; Guidelines; Health; Hepatic; Hepatic Stellate Cell; Hepatocyte; Human; Hyperlipidemia; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Inhibition of Apoptosis; Injury; Investigation; Kidney; Lead; Ligands; Lipids; Liver; Liver Failure; Liver Fibrosis; Lung; Macrophage; Manuscripts; Mediating; Medical; Medicine; Metabolic; Metabolism; Molecular; Molecular Mechanisms of Action; Morbidity - disease rate; Mus; Myofibroblast; National Institute of Diabetes and Digestive and Kidney Diseases; Oncology; Oral; Oral Administration; Organ; Orthopedics; Pathogenesis; Pathologic; Pathology; Pathway interactions; Phase; Phenotype; Phosphorylation; Population; Predisposition; Prevention; Primary carcinoma of the liver cells; Proliferating; Property; Protein-Lysine 6-Oxidase; Public Health; Publishing; Publishing Peer Reviews; Receptor Signaling; Reporting; Role; Safety; Series; Signal Pathway; Signal Transduction; Small Business Innovation Research Grant; Smooth Muscle; Structure-Activity Relationship; TGFB1 gene; TLR2 gene; TLR4 gene; Testing; Therapeutic; Tissues; Toll-like receptors; Toxicokinetics; Toxicology; Transforming Growth Factor beta; Tyrosine Kinase Receptor Inhibition; Virus Diseases; alcohol exposure; analog; antagonist; apolipoprotein E-3; clinically significant; connective tissue growth factor; culture plates; cytokine; drug candidate; efficacy evaluation; fatty liver disease; humanized mouse; improved; in vivo; inhibitor; kinase inhibitor; liver injury; liver transplantation; mortality; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel drug class; pandemic disease; patient population; pre-clinical; response; safety study; small molecule; stellate cell; therapeutic development; tissue culture; transcriptome sequencing; western diet; wound healing

ABSTRACT Pathologic tissue fibrosis, impelled by uncontrolled wound healing responses to acute or chronic injury is a significant problem in many organs including kidney, lung, and liver. Liver fibrosis is a major health problem that causes morbidity and mortality in the affected patient population. Liver fibrosis occurs in various pathologies including chronic alcohol exposure, non-alcoholic fatty liver disease (NAFLD) that can lead to non- alcoholic steatohepatitis (NASH), and viral infection, and can lead to cirrhosis and hepatocellular carcinoma. A number of molecular mechanisms have been scrutinized to identify the root causes of liver fibrosis. Among these, prominent studies point to aberrant Hedgehog (Hh) and transforming growth factor-β (TGF-β) signaling as prime factors underlying the pathogenesis of liver fibrosis, and hence extensively investigated. Accumulating evidence also suggests the role of Toll-Like Receptors (TLRs) in mediating the inflammatory responses of liver cells to endogenous factors and bacterial products present in the liver in NAFLD and NASH. At MAX BioPharma, we have identified semi-synthetic oxysterols that act as Hh pathway modulators, both as agonists and antagonists. We found oxysterol Hh pathway antagonists that also have potent inhibitory effects on TGF-β signaling in fibroblastic cells and in primary human hepatic stellate cells (HSC). With support from an SBIR Phase 1 grant from NIDDK, we recently published findings about the anti-NASH properties of an oxysterol analogue, Oxy210, that has led to the present application. Oxy210 has anti-fibrotic as well as anti- inflammatory properties that are mediated through inhibition of Hh, TGF-β and TLR signaling. Oxy210 induced robust inhibitory effects in a humanized hyperlipidemic mouse model of NASH, ApoE*3-Leiden.CETP mice on a high fat Western Diet, evidenced by inhibition of hepatic lipid deposition, inflammatory cytokine expression and fibrosis, associated with reduced hepatic cell apoptosis and improved circulating ALT levels. Based on these properties of Oxy210, in addition to its favorable pharmacokinetic and safety profiles, oral availability, and scalability, in the present SBIR Phase 2 application we propose to continue the examination of the disease modifying effects of Oxy210 in ApoE*3-Leiden.CETP mice in reversing already established disease in contrast to our published report when Oxy210 was administered at the initiation of the disease. We propose to identify the molecular and cellular mechanisms of anti-NASH properties of Oxy210 by performing metabolic tests as well as RNA-sequencing studies in livers of NASH mice with or without Oxy210 treatment. We propose to perform non-GLP in vitro and in vivo safety studies that will provide essential information for future IND-enabling GLP studies required in our anticipated IND filing for Oxy210 as a first-in-class new drug candidate for targeting NASH. NASH is a huge unmet medical need since there are no FDA approved therapies, leaving a large global population susceptible to severe liver failure and the need for liver transplantation.

摘要