C/EBP-beta PEPTIDES FOR THE TREATMENT OF LIVER INJURY AND FIBROSIS

用于治疗肝损伤和纤维化的 C/EBP-β 肽

基本信息

批准号：
8592994
负责人：
MARTINA BUCK
金额：
$ 30.69万
依托单位：
XFIBRA, LLC
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-05 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8592994
关键词：
Accounting Acute Agreement Alcoholism Animals Apoptosis Area Autopsy Biological Assay Biological Availability Body Weight decreased CCAAT-Enhancer-Binding Proteins Cells Chronic Cicatrix Cirrhosis Clinical Clinical Trials Collagen Development Diabetes Mellitus Dose Drug Kinetics Drug or chemical Tissue Distribution Excretory function Fatty Liver Fibrosis Future Hepatic Fibrogenesis Hepatic Stellate Cell Hepatitis B Hepatitis C Hepatocyte Histology Human In Vitro Inflammation Injury Kidney Knowledge Laser Microscopy Lead Leucine Zippers Libraries Liver Liver Cirrhosis Liver Fibrosis Lung Malignant neoplasm of liver Mass Spectrum Analysis Maximum Tolerated Dose Medical Messenger RNA Metabolic Modeling Morbidity - disease rate Mus Obesity Oral Administration Patients Penetration Peptides Peptoids Pharmaceutical Preparations Phase Phosphorylation Plasma Population Pre-Clinical Model Prevention Primary carcinoma of the liver cells Procedures RNA Recovery Research Sampling Schedule Serum Small Business Technology Transfer Research Testing Therapeutic Therapeutic Agents Thioacetamide Time Tissues Toxic effect Toxicogenomics Toxicokinetics Toxicology Transactivation Transgenes Work analog base caspase-8 chronic liver disease effective therapy fibrogenesis immunogenicity improved in vivo liquid chromatography mass spectrometry liver injury metabolic abnormality assessment mortality mouse model preclinical study prevent public health relevance research and development sex therapeutic target urinary

项目摘要

DESCRIPTION (provided by applicant): Activation of hepatic stellate cells (HSC) is responsible for the development of liver fibrosis in chronic liver diseases of all causes and remarkably, HSC clearance by apoptosis may allow recovery from liver injury and reversal of liver fibrosis. There is full agreement among liver fibrosis experts that inhibiting o reversing HS activation (the therapeutic target) is critical for the treatment of liver fibrosis. Both regressio of liver fibrosis as well as lack of progression of liver fibrosis, in spite of continued liver injury as we clearly documented in our pre-clinical studies, are considered important clinical targets for patients with chronic liver disease and liver fibrosis. Finally, blocking the progression of liver fibrosis would decrease development of primary liver cancer in these patients since the majority of hepatocellular carcinomas arise in cirrhotic livers. The basis for our Research and Development of the Ac-KAVD-CHO related peptoids are the following: i] that the nonphosphorylatable C/EBP¿-Ala217 transgene prevents phosphorylation of endogenous C/EBP¿, and activates caspase 8 resulting in apoptosis of HSC upon their activation, preventing progression and inducing regression liver fibrosis; ii] that neither the transactivation nor the leucine zipper domains are required for these effects; and iii] that a cell permeant tetrapeptide containing the RSK phosphoacceptor domain of C/EBP¿ is sufficient to replicate these effects . We created a library using analog synthesis to improve potential pitfalls for human use; ii] use in a step-wise manner assays to select the safest and most efficient peptides (including apoptosis assays in activated primary human HSC; cell-free caspase 8 activation assays; acute liver injury/fibrogenesis models; toxicology assays in highly differentiated, primary human hepatocyte cultures and mice). We have developed effective antifibrotic compounds with expected decreased immunogenicity and improved stability and bioavailability during clinical trials. The proposed compounds markedly inhibit activation of human and mouse hepatic stellate cells in culture and in vivo in preclinical models of liver fibrosis and decreased liver injury. These compounds were not toxic in the preliminary toxicology studies, including toxicogenomics, to highly differentiated hepatocytes and mice at least at 100-fold the therapeutic dose. The aims that are proposed for completion by this STTR are: Chronic liver fibrogenesis assays in mouse models; Pharmacokinetics; In Vitro ADMET Studies :Metabolic stability; CYP-450 Inhibition; and Exploratory Toxicology; Dose Escalation Study and Repeat-Dose Range-finding Toxicity Study. There is no medication for the treatment or prevention of liver fibrosis. Completion of these tasks for the proposed compounds will allow us proceeding with a Phase-2 STTR and clinical development in patients with liver fibrosis.

描述（由申请人提供）：肝星状细胞（HSC）的激活是所有原因引起的慢性肝病中肝纤维化的发生的原因，并且不常见的是，HSC通过细胞凋亡的清除可以使肝损伤恢复并逆转肝纤维化。肝纤维化专家一致认为，抑制或逆转 HS 激活（治疗靶点）对于肝纤维化的消退和治疗至关重要。尽管我们在临床前研究中清楚地记录了持续的肝损伤，但肝纤维化的进展被认为是慢性肝病和肝纤维化患者的重要临床目标。最后，阻止肝纤维化的进展将减少发展。由于大多数肝细胞癌发生在肝硬化肝脏中，因此我们研究和开发 Ac-KAVD-CHO 相关肽的基础如下： i] 非磷酸化的。 C/EBP?? -Ala217 转基因可防止内源性 C/EBP 磷酸化¿ ，并激活 caspase 8，激活后导致 HSC 凋亡，防止进展并诱导肝纤维化消退；ii] 这些作用不需要反式激活或亮氨酸拉链结构域；以及 iii] 含有 RSK 的细胞渗透性四肽； C/EBP 磷酸受体结构域¿足以复制这些效果我们使用模拟合成创建了一个库来改善人类使用的潜在缺陷；逐步分析以选择最安全和最有效的肽（包括激活的原代人 HSC 中的细胞凋亡分析；无细胞 caspase 8 激活分析；急性肝损伤/纤维发生模型；高度分化的原代人肝细胞培养物中的毒理学分析和我们开发了有效的抗纤维化化合物，在临床试验中预期会降低免疫原性并提高稳定性和生物利用度。所提出的化合物可显着抑制培养中的人和小鼠肝星状细胞的活化。在肝纤维化和损伤减少的临床前模型中，这些化合物在初步毒理学研究（包括毒理基因组学）中对高度分化的肝细胞和小鼠至少在100倍治疗剂量下没有毒性。该 STTR 包括：小鼠模型中的慢性肝纤维化测定；体外 ADMET 研究：CYP-450 抑制；毒理学；剂量递增研究和重复剂量范围探索毒性研究没有药物可以治疗或预防所提议的化合物，这将使我们能够继续进行 2 期 STTR 和临床开发。肝纤维化患者。