A hepatocyte-specific R-spondin mimetic bispecific fusion protein to stimulate hepatocyte regeneration in patients with acute alcoholic hepatitis

一种肝细胞特异性 R-spondin 模拟双特异性融合蛋白，可刺激急性酒精性肝炎患者的肝细胞再生

• 批准号: 10269934
• 负责人: Jay Tibbitts
• 金额: $ 50.25万
• 依托单位: SURROZEN OPERATING, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-25 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10269934
• 关键词: Abdominal Cavity; Acetaminophen; Acute Alcoholic Hepatitis; Alcohol-Induced Disorders; Alcoholic Hepatitis; Alcoholic Liver Diseases; Animal Model; Antibodies; Ascites; Benefits and Risks; Biological Assay; Biological Markers; Cell Line; Child; Chimeric Proteins; Clinical; Clinical Research; Clinical Trials; Clinical assessments; Clone Cells; Development; Disease model; Dose; Drug Kinetics; Fatigue; Fibrosis; Formulation; Gene Activation; Grant; Hepatic Encephalopathy; Hepatocyte; Homeostasis; Human; Icterus; Impairment; Infection; Inflammatory; Informed Consent; Ligands; Liver; Liver Cirrhosis; Liver Regeneration; Liver diseases; Manufactured Materials; Measures; Metabolic; Methods; Modeling; Monitor; Morbidity - disease rate; Mus; Mutate; Natural regeneration; Nature; Partial Hepatectomy; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pharmacology Study; Pharmacology and Toxicology; Phase; Play; Process; Proteins; Regimen; Regulation; Rodent; Rodent Diseases; Role; Running; Safety; Serum; Signal Transduction; Signs and Symptoms; Steroids; Testing; Tissues; Toxicology; WNT Signaling Pathway; beta catenin; cross reactivity; effective therapy; human tissue; improved; injured; interest; liver development; liver function; liver injury; liver repair; liver transplantation; manufacturing process; mimetics; mortality; mouse model; nonhuman primate; novel therapeutic intervention; novel therapeutics; pre-clinical; preclinical study; predicting response; receptor; regeneration following injury; sobriety; tissue regeneration; tissue repair

Abstract Alcoholic hepatitis (AH) is characterized by inflammatory liver injury with impaired hepatocyte regeneration, with high rates of morbidity and mortality. Currently, steroids are the only treatment option for patients with severe AH, however, they have limited efficacy (no treatment benefit demonstrated beyond 28 days) and many patients have contra-indications to steroid use (e.g. active infections) and cannot be treated. There is a clear unmet need for new therapeutic approaches in AH. Wnt signaling plays an important role in liver development, metabolic zonation, homeostatic turnover of hepatocytes, hepatocyte differentiation and maturation, and normal function and regulation of hepatocytes. Furthermore, Wnt/β-catenin signaling is critical to hepatocyte regeneration following various forms of liver injury. Deletion or overactivation of β-catenin has been shown to have a key impact on hepatocyte regeneration following partial hepatectomy, acetaminophen, CCl4, or alcohol-induced injuries in animal models. R-spondins (RSPOs) play an important role in liver homeostasis and hepatocyte regeneration following injury such as partial hepatectomy. RSPOs enhance Wnt signaling, and RSPO function depends on the presence of endogenous Wnt ligands; endogenous Wnt ligands tend to be upregulated and localized in injured tissues. Importantly in human AH patients, lack of hepatocyte regeneration and maturation is a major issue. Surrozen has developed SZN-043, a bi-specific fusion protein which is an R-spondin mimetic targeted to the hepatocyte receptor ASGR1 for liver-specific enhancement of Wnt signaling and tissue regeneration and repair. Our studies suggest that the effects of SZN-043, in contrast to RSPO2, are highly specific to hepatocytes, and can improve liver function and reduce fibrosis in rodent disease models. Our preclinical studies in mice and non-human primates have demonstrated that SZN-043 induces Wnt-target gene activation in the liver and selectively stimulates proliferation and maturation of hepatocytes. We are interested in exploring whether SZN-043 is capable of improving liver function and/or fibrosis in AH. In this grant, we propose first moving forward to develop cell line and material manufacturing process for SZN-043. This will be followed by IND-enabling studies, including, pharmacology, toxicology, pharmacokinetics, and biomarker information to inform and enable safe and effective administration of SZN-043 for testing in humans. We will then conduct Phase 1 single- and multiple-ascending dose studies in human patients to assess pharmacokinetics, pharmacodynamics, and safety of SZN-043 for the treatment of AH.

摘要