AAV-Mediated Gene Delivery to the Mouse Liver

Area of Science:

• Hepatology
• Gene Therapy
• Molecular Virology

Background:

• The liver is a primary target for gene therapy due to frequent liver disease.
• Adeno-associated viral vectors (AAV) are widely used for liver-directed gene delivery due to high efficiency and available tropism.
• AAV episomal genomes lead to less stable gene expression in replicating, growing livers, posing challenges for studies in young animals.

Purpose of the Study:

• To provide a technical overview of adeno-associated viral vector (AAV)-mediated gene transfer in the mouse liver.
• To highlight considerations for experimental design involving AAV in young, growing mouse models.
• To discuss the utility of xenograft models for AAV vector evaluation.

Main Methods:

• Focus on adeno-associated viral vector (AAV) transduction in mouse liver models.
• Exploration of AAV-mediated gene transfer in xenograft models with chimeric mouse-human livers.
• Discussion of vector development and in vivo capsid selection.

Main Results:

• AAV vectors demonstrate high transduction efficiency in the adult liver.
• Episome clearance during hepatocellular replication reduces gene expression stability in growing livers.
• Xenograft models show promise for selecting and characterizing human-specific AAV capsids.

Conclusions:

• Understanding AAV genome stability is crucial for gene therapy research in young animal models.
• Mouse liver models are invaluable for studying liver pathophysiology and developing new therapeutics.
• Xenograft models may offer improved prediction of clinical vector performance compared to nonhuman primates.