Improving Drug Discovery by Nucleic Acid Delivery in Engineered Human Microlivers

Area of Science:

• Hepatology and Drug Development
• Bioengineering and Regenerative Medicine
• Genomics and Therapeutics

Background:

• Human liver metabolism and xenobiotic processing differ significantly from model organisms, hindering accurate drug toxicity and efficacy testing.
• Existing models lack the robustness and predictive power needed for advancing small molecule and nucleic acid therapeutic pipelines.
• There is a critical need for advanced, functional human liver models to accelerate therapeutic development.

Purpose of the Study:

• To develop and validate a novel bioengineered human liver model for enhanced drug discovery.
• To demonstrate the utility of this model for predicting small molecule efficacy and toxicity.
• To showcase its application in testing nucleic acid therapeutics, including small interfering RNAs (siRNAs).

Main Methods:

• Fabrication of a functionally stable, multi-well bioengineered microliver using primary human hepatocytes and stromal cells.
• Application of a new modality for robust and durable gene silencing in vitro.
• Testing of small interfering RNAs (siRNAs) targeting hepatocytes within the engineered liver model.

Main Results:

• Achieved robust and durable gene silencing in the engineered liver model.
• Demonstrated the model's capacity to tune human metabolism of small molecules.
• Successfully queried the potential efficacy and/or toxicity of candidate therapeutics, including siRNAs.

Conclusions:

• The bioengineered microliver platform offers a powerful tool for advancing small molecule and nucleic acid therapeutic pipelines.
• This model provides a more predictive and functional in vitro system for assessing drug safety and efficacy.
• The platform has significant potential for impacting human liver genetic and infectious disease research and treatment.