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.

据估计，西方世界 20-30% 的成年人患有非酒精性脂肪肝 (NAFLD)。最多 NAFLD 是良性的，但高达 30% 的 NAFLD 患者会发展为进行性脂肪肝，称为脂肪肝 非酒精性脂肪性肝炎（NASH）。 NASH 是严重肝病的主要原因，造成超过 1,750 亿美元的损失 未来二十年美国的医疗保健费用将会增加，并且 NASH 患病率正在上升。早期诊断 NASH 通过生活方式干预可能会逆转。不幸的是，区分 NASH 和良性脂肪的唯一方法 肝脏是通过侵入性活检进行的，这对于重复采样来监测疾病进展或情况是不切实际的 治疗反应。因此，NASH 早期无创检测的需求尚未得到满足。 第二个未满足的主要需求是缺乏评估 NASH 治疗反应的无创方法。 NASH 的组织学评分基于脂肪变性、肝细胞气球样变、炎症、 和纤维化；然而，纤维化是与肝硬化、肝细胞性肝病进展相关的唯一组织学特征。 癌症或肝功能衰竭。对推动疾病进展的 NASH 疾病活动进行无创成像的技术 肝纤维化的发生可能会深刻改变我们诊断 NASH 和监测治疗反应的能力。血清 生物标志物组合和超声或磁共振（MR）弹性成像方法可以合理地检测肝脏 纤维化处于非常晚期阶段 (F4)，但无法有效检测纤维化的早期阶段 (F1、F2)，并且没有 这些技术已被证明可以有效地在临床试验中监测治疗反应。这些 未满足的需求还延伸到其他慢性肝病，例如肝脏疾病。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钆 (Gd) 的 MR 成像探头，能够量化 纤维发生——胶原交联和纤维化发生的疾病活动过程——通过 胶原蛋白交联过程中产生的细胞外蛋白质结合醛的分子靶向。我们有 动物模型表明，纤维发生的分子 MR 对于早期纤维化检测具有极高的敏感性 也是治疗反应的早期报告者，无创地检测积极的组织重塑过程 在减少肝纤维化之前。然而，由于Gd基成像探针的安全性，人们对它的安全性存在担忧。 Gd 保留和毒性，从而限制了基于 Gd 的探针的商业潜力。 Reveal Pharma 开发了专有的“RVP”锰螯合物技术来替代 Gd 的使用 先生代理。在此快速通道应用中，我们将开发一种无 Gd 纤维发生特异性 MR 成像探针。在 第一阶段，我们将合成探针库并在小鼠模型中展示纤维发生特异性成像 NASH 的。在第二阶段，我们将进行先导化合物优化；选择候选“RVP-FI”进行最终临床 发展;并在不同的动物模型中验证其安全性和实用性。结果将是高度敏感的 MR 纤维发生探针已证明体内功效和安全性，准备进行临床开发。