Nonalcoholic fatty liver disease (NAFLD) affects an estimated 20-30% of adults in the western world. MostNAFLD is benign, but up to 30% of NAFLD patients will develop a progressive form of fatty liver termednonalcoholic steatohepatitis (NASH). NASH is the leading cause of severe liver disease, leading to >$175 billionin healthcare costs over the next two decades in the US, and NASH prevalence is rising. Diagnosed early, NASHmay be reversed with lifestyle intervention. Unfortunately, the only way to distinguish NASH from benign fattyliver is through invasive biopsy, which is impractical for repeated sampling to monitor disease progression ortreatment 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, hepatocellularcarcinoma or liver failure. Technology to noninvasively image NASH disease activity which drives progressionof liver fibrosis could profoundly alter our ability to diagnose NASH and monitor treatment response. Serumbiomarker panels and ultrasound or magnetic resonance (MR) elastography methods can reasonably detect liverfibrosis at very advanced stages (F4) but are ineffective at detecting earlier stages of fibrosis (F1, F2), and noneof these techniques have been shown to be effective in monitoring treatment response in clinical trials. Theseunmet 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 quantifyingfibrogenesis - the disease activity process by which collagen is crosslinked and fibrosis occurs - throughmolecular targeting of extracellular protein-bound aldehydes generated during collagen crosslinking. We haveshown in animal models that molecular MR of fibrogenesis has exquisite sensitivity for early fibrosis detectionand is also an early reporter of treatment response, noninvasively detecting positive tissue remodeling processesprior to reduction in liver fibrosis. However, there is concern about the safety of Gd-based imaging probes dueto 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 inMR agents. In this Fast Track application we will develop a Gd-free fibrogenesis-specific MR imaging probe. InPhase I we will synthesize a library of probes and demonstrate fibrogenesis-specific imaging in a mouse modelof NASH. In Phase II, we will perform lead optimization; select a candidate "RVP-FI" for ultimate clinicaldevelopment; and validate both its safety and utility in different animal models. The result will be a highly sensitiveMR fibrogenesis probe with demonstrated in vivo efficacy and safety, poised for clinical development.
Public Health Relevance Statement: Project Narrative
Liver fibrogenesis is the active scarring of liver tissue that occurs in chronic liver diseases like nonalcoholic
steatohepatitis (NASH). If left unattended liver fibrosis can progress to liver failure, cirrhosis, or primary liver
cancer. There are no methods to noninvasively detect and quantify fibrogenesis. The goal of this project is to
develop a magnetic resonance imaging (MRI) probe that can detect fibrogenesis, monitor disease progression
and drug treatment response, and is safe for human use.
Project Terms: <21+ years old> 