Fibrogenesis Targeted Manganese Based MRI Contrast Agent

纤维发生靶向锰基 MRI 造影剂

• 批准号: 10547505
• 负责人: Vera Hoffman
• 金额: $ 29.04万
• 依托单位: REVEAL PHARMA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10547505
• 关键词: Adult; Affect; Affinity; Age; Alcoholic steatohepatitis; Aldehydes; Animal Model; Benign; Binding; Binding Proteins; Biopsy; Blood; Cardiotoxicity; Chelating Agents; Cholestasis; Cicatrix; Cirrhosis; Clinical Trials; Collagen; Complex; Contrast Media; Detection; Development; Diagnosis; Diet; Disease; Disease Progression; Dissociation; Dose; Drug Kinetics; Early Diagnosis; Extracellular Protein; Fatty Liver; Fibrosis; Gadolinium; Goals; Health Care Costs; Healthcare; Hepatic Fibrogenesis; Hepatocyte; Histologic; Human; Image; Immune; In Vitro; Inflammation; Kinetics; Left; Libraries; Ligation; Link; Liver; Liver Failure; Liver Fibrosis; Liver diseases; Magnetic Resonance; Magnetic Resonance Elastography; Magnetic Resonance Imaging; Manganese; Maximum Tolerated Dose; Metabolism; Methods; Microsomes; Modeling; Molecular Target; Monitor; Monkeys; Mus; Muscle; Noise; Non-Invasive Cancer Detection; Onset of illness; Patients; Pharmacotherapy; Phase; Prevalence; Primary Malignant Neoplasm of Liver; Primary carcinoma of the liver cells; Process; Proteins; Rattus; Reporter; Resolution; Safety; Sampling; Series; Serum; Structure-Activity Relationship; Techniques; Technology; Tissues; Toxic effect; Toxicokinetics; Toxicology; Treatment Efficacy; Western World; analog; base; bile duct; biomarker panel; chronic liver disease; clinical development; cost effective; crosslink; dietary; early detection biomarkers; fibrogenesis; genotoxicity; imaging probe; in vivo; lead candidate; lead optimization; lifestyle intervention; lipophilicity; molecular modeling; mouse model; non-alcoholic fatty liver disease; non-invasive imaging; nonalcoholic steatohepatitis; preclinical development; predictive marker; primary sclerosing cholangitis; screening; treatment response; ultrasound; uptake

Nonalcoholic fatty liver disease (NAFLD) affects an estimated 20-30% of adults in the western world. Most NAFLD is benign, but up to 30% of NAFLD patients will develop a progressive form of fatty liver termed nonalcoholic steatohepatitis (NASH). NASH is the leading cause of severe liver disease, leading to >$175 billion in healthcare costs over the next two decades in the US, and NASH prevalence is rising. Diagnosed early, NASH may be reversed with lifestyle intervention. Unfortunately, the only way to distinguish NASH from benign fatty liver is through invasive biopsy, which is impractical for repeated sampling to monitor disease progression or treatment response. Thus there is a major unmet need for the noninvasive detection of NASH at an early stage. A second major unmet need is the lack of a noninvasive method to assess treatment response in NASH. Histologic scoring of NASH is based on the presence of steatosis, hepatocellular ballooning, inflammation, and fibrosis; however fibrosis is the only histologic feature that is linked to progression to cirrhosis, hepatocellular carcinoma or liver failure. Technology to noninvasively image NASH disease activity which drives progression of liver fibrosis could profoundly alter our ability to diagnose NASH and monitor treatment response. Serum biomarker panels and ultrasound or magnetic resonance (MR) elastography methods can reasonably detect liver fibrosis at very advanced stages (F4) but are ineffective at detecting earlier stages of fibrosis (F1, F2), and none of these techniques have been shown to be effective in monitoring treatment response in clinical trials. These unmet needs extend to other chronic liver diseases, e.g. primary sclerosing cholangitis, alcoholic steatohepatitis. We recently developed a class of gadolinium (Gd)-based MR imaging probes that are capable of quantifying fibrogenesis – the disease activity process by which collagen is crosslinked and fibrosis occurs – through molecular targeting of extracellular protein-bound aldehydes generated during collagen crosslinking. We have shown in animal models that molecular MR of fibrogenesis has exquisite sensitivity for early fibrosis detection and is also an early reporter of treatment response, noninvasively detecting positive tissue remodeling processes prior to reduction in liver fibrosis. However, there is concern about the safety of Gd-based imaging probes due to Gd retention and toxicity, thus limiting the commercial potential of Gd-based probes. Reveal Pharma has developed proprietary “RVP” manganese-chelate technology to replace the use of Gd in MR agents. In this Fast Track application we will develop a Gd-free fibrogenesis-specific MR imaging probe. In Phase I we will synthesize a library of probes and demonstrate fibrogenesis-specific imaging in a mouse model of NASH. In Phase II, we will perform lead optimization; select a candidate “RVP-FI” for ultimate clinical development; and validate both its safety and utility in different animal models. The result will be a highly sensitive MR fibrogenesis probe with demonstrated in vivo efficacy and safety, poised for clinical development.

非酒精性脂肪肝疾病（NAFLD）影响西方世界中20-30％的成年人。最多 NAFLD是良性的，但是多达30％的NAFLD患者会发展出一种累进的脂肪肝脏形式 非酒精性脂肪性肝炎（NASH）。纳什（Nash）是严重肝病的主要原因，导致1750亿美元 在美国未来二十年的医疗费用中，纳什的患病率正在上升。早期诊断出纳什 生活方式干预可能会扭转。不幸的是，将纳什与良性脂肪区分开的唯一方法 肝脏是通过侵入性活检，对于重复采样以监测疾病进展或 治疗反应。在早期阶段对纳什的无创检测有很大的未满足。 第二个主要的未满足需要是缺乏评估NASH治疗反应的无创方法。 NASH的组织学评分是基于脂肪变性，肝细胞气囊，炎症， 和纤维化；但是，纤维化是与肝硬化有关的唯一与肝硬化有关的组织学特征 癌或肝衰竭。无创图像纳什疾病活动的技术驱动进展 肝纤维化可能会深刻地改变我们诊断NASH和监测治疗反应的能力。血清 生物标志物面板和超声或磁共振（MR）弹性图方法可以合理地检测肝脏 在非常高级阶段（F4）的纤维化，但在检测早期纤维化阶段（F1，F2）方面无效，没有 这些技术已被证明在临床试验中有效监测治疗反应。这些 未满足的需求扩展到其他慢性肝病，例如原发性硬化性胆管炎，酒精性脂肪性肝炎。 我们最近开发了一类基于gdolinium（GD）的MR成像问题，能够量化 纤维化 - 胶原蛋白交联并发生纤维化的疾病活动过程 - 胶原交联期间产生的细胞外蛋白结合醛的分子靶向。我们有 在动物模型中显示的纤维发生的分子MR对早期纤维化检测具有独特的敏感性 并且也是治疗反应的早期记者，非侵入性检测阳性组织重塑过程 在减少肝纤维化之前。但是，人们担心基于GD的成像问题的安全性 GD保留和毒性，从而限制了基于GD问题的商业潜力。 揭示Pharma已开发了专有的“ RVP”锰氯酸盐技术，以取代GD在 代理商先生。在此快速轨道应用中，我们将开发无GD纤维化特异性MR成像探针。在 第一阶段我们将合成问题库，并在小鼠模型中证明特异性成像 纳什。在第二阶段，我们将执行铅优化；选择候选人“ RVP-FI”以进行最终临床 发展;并在不同动物模型中验证其安全性和效用。结果将是一个高度敏感的 MR纤维发生探针具有体内效率和安全性，为临床发育中毒。