Analysis of Adeno-Associated Virus Tropism in Mice: A Comprehensive Survey of AAV Serotypes

Adeno-associated viruses (AAVs) have become essential tools in gene therapy due to their ability to deliver genetic material into targeted tissues efficiently. Recent studies have focused on understanding the tropism—or tissue-targeting abilities—of various AAV serotypes, which is critical for optimizing therapeutic efficacy. This article summarizes an in-depth analysis of the tropism of ten naturally occurring AAV serotypes (AAV3B, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAVrh8, AAVrh10, and AAVrh74) following systemic delivery in mice. The research provides key insights into how different AAV serotypes behave in male and female subjects, expanding the understanding of tissue-specific targeting for gene therapy applications.

Key Findings:

1. Liver Tropism: All AAV serotypes, except for AAV3B and AAV4, demonstrated a strong preference for liver tissue. This makes them highly effective candidates for liver-targeted therapies.
2. Unexpected Tissue Transduction: Fluorescence activation revealed that several serotypes also transduced tissues beyond their expected targets, such as the adrenal glands, testes, and ovaries, emphasizing the importance of analyzing off-target effects in gene therapy.
3. Pan-Endothelial Tropism of AAV4: Unlike the other serotypes, AAV4 exhibited a unique ability to target endothelial cells across multiple tissues, including the pancreas’ beta cells. This discovery opens new avenues for designing therapies that focus on vascular and endocrine systems.
4. Sexual Dimorphism in Tropism: There were notable differences in AAV tropism between male and female mice, particularly in liver transduction. Male mice showed higher levels of liver transduction for most serotypes, while AAVrh74 displayed a preference for transduction in female mice.
5. Biodistribution Correlation: The distribution of AAV genomes across different tissues generally aligned with the observed fluorescence-based transduction, except for immune-related tissues. This reinforces the value of combining genetic and fluorescence data to assess AAV efficacy and targeting.

Implications for Gene Therapy

Understanding the tropism of AAV serotypes is crucial for tailoring gene therapy strategies to specific tissues and reducing unintended side effects. For example, the strong liver tropism of most AAV serotypes supports their continued use in liver-targeted therapies, such as those for hemophilia or metabolic disorders. However, the discovery of non-target transduction in tissues like the adrenal glands and reproductive organs highlights the need for careful consideration of off-target effects in therapeutic designs.

Additionally, the identification of AAV4’s pan-endothelial tropism suggests potential for endothelial cell-targeted therapies, which could benefit treatments for vascular diseases or diabetes through pancreatic beta-cell targeting.

Future Directions

This comprehensive resource of AAV tropism data offers valuable guidance for researchers selecting the most suitable AAV serotype for preclinical studies in mice. Moving forward, comparisons between these mouse models and non-human primates, as well as clinical outcomes in humans, will be critical in advancing gene therapy treatments. These cross-species analyses could help streamline the transition from experimental models to human therapies.

This atlas of AAV tropism in mice, along with associated images and data, is publicly available for further exploration and application in gene therapy research through the Somatic Cell Genome Editing Consortium Toolkit.

This detailed study on AAV tropism in mice helps advance gene therapy by revealing critical insights into the tissue-targeting capabilities of different AAV serotypes, supporting both basic research and clinical applications.

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