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

描述（由申请人提供）：肝星状细胞（HSC）的激活与各种原因的慢性肝病肝纤维化的发展有关，值得注意的是，通过细胞凋亡清除HSC可能允许肝损伤恢复和肝纤维化逆转。肝纤维化专家一致认为，抑制或逆转HS激活（治疗靶点）对肝纤维化的治疗至关重要。正如我们在临床前研究中明确记载的那样，尽管肝损伤持续存在，但肝纤维化的消退和无进展被认为是慢性肝病和肝纤维化患者的重要临床靶点。最后，阻断肝纤维化的进展将减少这些患者原发性肝癌的发展，因为大多数肝细胞癌发生在肝硬化中。我们研究和开发Ac-KAVD-CHO相关肽的基础如下：i]不可磷酸化的C/EBP¿-Ala217转基因阻止内源性C/EBP¿的磷酸化，并激活caspase 8，导致HSC活化后凋亡，阻止其进展并诱导退行性肝纤维化；Ii]这些作用既不需要交换激活也不需要亮氨酸拉链结构域；iii]含有C/EBP¿的RSK磷受体结构域的细胞渗透四肽足以复制这些效应。我们使用模拟合成创建了一个库，以改善人类使用的潜在陷阱；使用于

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.