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.

在西方世界，非酒精性脂肪性肝病（NAFLD）影响了大约20-30%的成年人。大多数