Adeno-associated virus (AAV) capsid engineering in liver-directed gene therapy

ABSTRACT

Introduction: Gene therapy clinical trials with adeno-associated virus (AAV) vectors report impressive clinical efficacy data. Nevertheless, challenges have become apparent, such as the need for high vector doses and the induction of anti-AAV immune responses that cause the loss of vector-transduced hepatocytes. This fostered research focusing on development of next-generation AAV vectors capable of dealing with these hurdles.

Areas Covered: While both the viral vector genome and the capsid are subjects to engineering, this review focuses on the latter. Specifically, we summarize the principles of capsid engineering strategies, and describe developments and applications of engineered capsid variants for liver-directed gene therapy.

Expert Opinion: Capsid engineering is a promising strategy to significantly improve efficacy of the AAV vector system in clinical application. Reduction in vector dose will further improve vector safety, lower the risk of host immune responses and the cost of manufacturing. Capsid engineering is also expected to result in AAV vectors applicable to patients with preexisting immunity toward natural AAV serotypes.

KEYWORDS:

• Adeno-associated virus (AAV)
• AAV vectors
• capsid engineering
• site-directed mutagenesis
• capsid shuffling
• hepatocyte transduction
• liver-directed gene therapy

Acknowledgments

The authors thank Dr. Michael Morgan (MHH, Hannover) and Dr. Sergio López Manzaneda for critical reading the manuscript, and José Mateos Granados for his advice during preparation of the figures.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This work was supported in part by Universidad Autónoma de Madrid and Erasmus+ Practicas to ERM and the Deutsche Krebshilfe [109256, 70111950], the Federal Ministry of Education and Research-funded Professorinnenprogramm Niedersachsen, the German Research Foundation (DFG)-funded REBIRTH Cluster of Excellence, the REBIRTH Research Center for Translational Regenerative Medicine funded by the MWK Lower Saxony, and the American Foundation for AIDS Research (amfAR) to HB.