Fibrogenesis Targeted Manganese Based MRI Contrast Agent

非酒精性脂肪性肝病（NAFLD）影响西方世界估计20-30%的成年人。最 NAFLD是良性的，但高达30%的NAFLD患者会发展为脂肪肝的进行性形式， 非酒精性脂肪性肝炎（NASH）。NASH是严重肝脏疾病的主要原因，导致超过1750亿美元 在美国，未来20年的医疗保健成本将增加，NASH患病率正在上升。早期诊断，NASH 可以通过生活方式干预来逆转。不幸的是，区分NASH和良性脂肪肝的唯一方法 肝脏是通过侵入性活检，这是不切实际的重复采样，以监测疾病进展， 治疗反应。因此，在早期阶段对NASH的非侵入性检测存在主要未满足的需求。 第二个未满足的主要需求是缺乏评估NASH治疗反应的非侵入性方法。 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，纤维化是与进展为肝硬化、肝细胞性肝硬化和肝纤维化相关的唯一组织学特征。 癌症或肝功能衰竭。非侵入性成像NASH疾病活动的技术，推动进展 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）弹性成像方法可以合理地检测肝脏 在非常晚期的纤维化（F4），但在检测早期纤维化（F1，F2）无效， 这些技术中的一种已被证明在临床试验中监测治疗反应是有效的。这些 未满足的需求延伸到其他慢性肝病，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钆（Gd）的MR成像探头，能够定量 纤维化-胶原蛋白交联和纤维化发生的疾病活动过程-通过 胶原交联过程中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，纤维形成的分子MR对于早期纤维化检测具有极高的灵敏度 也是治疗反应的早期报告者，非侵入性地检测阳性组织重塑过程 在肝纤维化减少之前。然而，人们担心基于Gd的成像探针的安全性， Gd保留和毒性，从而限制了基于Gd的探针的商业潜力。 Reveal Pharma已开发出专有的“RVP”锰螯合物技术，以取代Gd的使用， MR探员。在此快速通道应用中，我们将开发一种无Gd纤维化特异性MR成像探头。在 第一阶段，我们将合成一个探针库，并在小鼠模型中展示纤维化特异性成像 关于NASH在第二阶段，我们将进行电极导线优化;选择候选“RVP-FI”用于最终临床 并在不同的动物模型中验证其安全性和实用性。结果将是一个高度敏感的 MR纤维化探针具有已证实的体内有效性和安全性，准备用于临床开发。

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.