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A Familial Hypercholesterolemia Human Liver Chimeric Mouse Model Using Induced Pluripotent Stem Cell-derived Hepatocytes
Published on: September 15, 2018
Liver-targeting chimeras as a potential modality for the treatment of liver diseases
Chuanjie Chen1, Yongzhang Pan2, Xiaoyu Yang3
1Drug Discovery & Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China.
Abstract:
Liver diseases pose significant challenges to global public health. In the realm of drug discovery and development, overcoming 'on-target off-tissue' effects remains a substantial barrier for various diseases. In this study, we have pioneered a Liver-Targeting Chimera (LIVTAC) approach using a proteolysis-targeting chimera (PROTAC) molecule coupled to the liver-specific asialoglycoprotein receptor (ASGPR) through an innovative linker attachment strategy for the precise induction of target protein degradation within the liver. As a proof-of-concept study, we designed XZ1606, a mammalian bromodomain and extra-terminal domain (BET)-targeting LIVTAC agent, which not only demonstrated enduring tumor suppression (over 2 months) in combination with sorafenib but also an improved safety profile, notably ameliorating the incidence of thrombocytopenia, a common and severe on-target dose-limiting toxic effect associated with conventional BET inhibitors. These encouraging results highlight the potential of LIVTAC as a versatile platform for addressing a broad spectrum of liver diseases.
Insights
A novel Liver-Targeting Chimera (LIVTAC) approach precisely degrades target proteins in the liver. This method, demonstrated with a BET-targeting agent, shows sustained tumor suppression and improved safety for liver disease treatment.
Area of Science:
- Biochemistry
- Pharmacology
- Oncology
Background:
- Liver diseases present significant global health challenges.
- On-target, off-tissue effects hinder drug development for various diseases.
- Targeted protein degradation offers a promising therapeutic strategy.
Purpose of the Study:
- To develop a Liver-Targeting Chimera (LIVTAC) for precise protein degradation in the liver.
- To evaluate a novel bromodomain and extra-terminal domain (BET)-targeting LIVTAC agent (XZ1606) as a proof-of-concept.
- To assess the efficacy and safety profile of LIVTAC in preclinical models.
Main Methods:
- Designed a LIVTAC molecule by conjugating a proteolysis-targeting chimera (PROTAC) to a liver-specific asialoglycoprotein receptor (ASGPR) ligand via a unique linker.
- Developed XZ1606, a mammalian BET-targeting LIVTAC agent.
- Evaluated XZ1606 in combination with sorafenib for tumor suppression and safety, focusing on thrombocytopenia.
Main Results:
- XZ1606 demonstrated sustained tumor suppression for over two months in combination therapy.
- The LIVTAC approach significantly improved the safety profile compared to conventional BET inhibitors.
- Incidence of thrombocytopenia, a common dose-limiting toxicity, was notably ameliorated.
Conclusions:
- The LIVTAC platform is a versatile strategy for targeted protein degradation within the liver.
- This approach holds potential for treating a wide range of liver diseases with enhanced safety.
- LIVTAC represents a significant advancement in precision medicine for liver-targeted therapies.
