Development of a Novel MRI Contrast Agent for Early Detection of Alcoholic Steatohepatitis

开发用于早期检测酒精性脂肪性肝炎的新型 MRI 造影剂

• 批准号: 10065310
• 负责人: Jenny J. Yang
• 金额: $ 98.99万
• 依托单位: INLIGHTA BIOSCIENCES, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-20 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10065310
• 关键词: Affinity; Alcoholic Liver Diseases; Alcoholic steatohepatitis; Alcohols; Animal Model; Animals; Antibodies; Autoimmune Hepatitis; Biological Assay; Canis familiaris; Cessation of life; Clinical; Clinical Trials; Collagen; Contrast Media; Cyclic GMP; Detection; Developed Countries; Development; Diagnosis; Diagnostic Procedure; Disease; Disease Progression; Drug Controls; Drug Kinetics; Early Diagnosis; Ensure; Exhibits; Face; Fermentation; Fibrosis; Formulation; GD3 Binding; Gadolinium; Gold; Heart; Hepatitis B; Hepatitis C; Heterogeneity; Hospitalization; Human; Interobserver Variability; Ions; Kidney; Liver; Liver Cirrhosis; Liver Failure; Liver Fibrosis; Liver diseases; Magnetic Resonance Elastography; Magnetic Resonance Imaging; Medical; Metals; Monitor; Morbidity - disease rate; Organ; Pain; Patients; Pattern; Pharmaceutical Preparations; Phase; Physiological; Portal Hypertension; Primary carcinoma of the liver cells; Procedures; Process; Proteins; Quality Control; Rattus; Resistance; Risk; Safety; Sampling Errors; Scaffolding Protein; Sensitivity and Specificity; Serum; Staging; Techniques; Technology; Testing; Time; Tissues; Toxic effect; Toxicokinetics; United States Food and Drug Administration; analytical method; angiogenesis; assay development; base; cGMP production; cell bank; chronic liver disease; clinical translation; dosage; effective therapy; elastography; high risk; immunogenicity; in vivo; innovation; intrahepatic; intravenous injection; liver biopsy; meetings; metal poisoning; molecular imaging; mortality; mortality risk; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; particle; process optimization; response; screening; treatment strategy

Abstract Chronic liver disease (CLD) is a major cause of morbidity and mortality worldwide[1-4]. Hepatic fibrosis can develop in patients with any type of chronic liver disease (CLD), including alcoholic liver disease (ALD), hepatitis C, hepatitis B, nonalcoholic fatty liver disease (NAFLD) and autoimmune hepatitis. The major clinical consequences of cirrhosis are liver failure and hepatocellular carcinoma (HCC), both of which increase the risk of death. Alcoholic liver disease (ALD) is a leading cause of liver disease and liver-related deaths globally, particularly in developed nations. The current gold standard diagnostic method, liver biopsy is invasive and has many limitations including sampling error and high inter-observer variability even for the diagnosis of advanced stages of liver fibrosis. None of several technologies investigated as alternatives offers the desired sensitivity and specificity for the early detection and staging of fibrosis. Thus, an innovative, safe MRI contrast agent is required to overcome several major limitations including low sensitivity and specificity for early stage fibrosis and detection in heterogeneous tissue. Our team has pioneered a new class of gadolinium based contrast agents which utilize a protein scaffold to bind Gd3+ atoms. We have shown that ProCA32.collagen, a collagen 1 targeted protein MRI contrast agent, exhibits strong affinity to collagen I, whose expression level and spatial pattern depend on the stage of fibrosis. ProCA32.collagen possesses high relaxivities per particle (r1 and r2) at both 1.4 and 7.0 T, which enables the robust detection of early-stage alcohol-induced liver fibrosis and nonalcoholic steatohepatitis in animal models via dual contrast modes. Our preliminary studies on toxicity profiles and in vivo stability of our compound in animals using non-GLP grade materials have provided confidence that the compound will exhibit good sensitivity and specificity for early detection of liver fibrosis in human clinical trials. In Phase I of this proposal, we seek timely support for conducting IND enabled CMC studies for generating GLP/cGMP grade ProCA32.collagen. In Phase II, we will conduct toxicity and safety profile studies using GLP/cGMP grade products to complete IND required studies for clinical trials.

抽象的 慢性肝病（CLD）是全世界发病和死亡的主要原因[1-4]。肝纤维化可 患有任何类型慢性肝病 (CLD) 的患者，包括酒精性肝病 (ALD)、肝炎 C、乙型肝炎、非酒精性脂肪肝病（NAFLD）和自身免疫性肝炎。主要临床 肝硬化的后果是肝功能衰竭和肝细胞癌（HCC），这两者都会增加风险 死亡。酒精性肝病（ALD）是全球肝脏疾病和肝脏相关死亡的主要原因， 尤其是在发达国家。目前的金标准诊断方法，肝活检是侵入性的，具有 即使对于高级疾病的诊断，也存在许多限制，包括采样误差和观察者间的高变异性 肝纤维化的阶段。作为替代品进行研究的几种技术均无法提供所需的灵敏度 以及纤维化早期检测和分期的特异性。因此，一种创新、安全的 MRI 造影剂是 需要克服几个主要限制，包括早期纤维化的低敏感性和特异性以及 异质组织中的检测。我们的团队开创了一种新型钆基造影剂 它利用蛋白质支架结合 Gd3+ 原子。我们已经证明 ProCA32.collagen，一种靶向胶原蛋白 1 蛋白质 MRI 造影剂，对 I 型胶原蛋白具有很强的亲和力，其表达水平和空间模式 取决于纤维化的阶段。 ProCA32.collagen 每个粒子（r1 和 r2）均具有 1.4 的高弛豫率 和 7.0 T，能够稳健检测早期酒精引起的肝纤维化和非酒精性肝纤维化 通过双重对比模式动物模型中的脂肪性肝炎。我们对毒性特征和体内的初步研究 我们的化合物在使用非 GLP 级材料的动物中的稳定性使我们相信 该化合物在人体临床试验中对肝纤维化的早期检测表现出良好的敏感性和特异性。 在本提案的第一阶段，我们寻求及时支持进行 IND 支持的 CMC 研究，以产生 GLP/cGMP 级 ProCA32.胶原蛋白。在第二阶段，我们将使用以下方法进行毒性和安全性研究： GLP/cGMP 级产品可完成临床试验 IND 所需的研究。