Serum APOA4 Pharmacodynamically Represents Administered Recombinant Human Hepatocyte Growth Factor (E3112)

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Hepatocyte growth factor (HGF) exhibits potent anti-apoptotic and tissue repair properties.
• Identifying reliable pharmacodynamic (PD) markers is crucial for evaluating HGF-based therapies.

Purpose of the Study:

• To identify and validate a novel PD marker for recombinant human HGF (rh-HGF).
• To investigate the c-Met dependency of the identified marker.

Main Methods:

• Administration of rh-HGF to mice and analysis of liver tissue for soluble protein candidates.
• In vitro validation using primary human hepatocytes and in vivo validation in an animal disease model.
• Assessment of c-Met dependency using specific inhibitors.

Main Results:

• Apolipoprotein A4 (APOA4) was identified as a gene significantly induced by rh-HGF in murine liver.
• rh-HGF treatment robustly increased APOA4 mRNA and protein levels in human hepatocytes, dependent on c-Met signaling.
• Serum APOA4 levels increased in mice following rh-HGF administration, including in an acute liver failure model, confirming its PD marker status.

Conclusions:

• APOA4 serves as a soluble PD marker for rh-HGF, demonstrating c-Met dependency.
• Clinical validation of APOA4's utility in healthy subjects and acute liver failure patients is warranted.