Next-generation AAV vectors for liver-directed gene therapy

Introduction

Liver-directed gene therapy has undergone significant development in the last two decades. Recombinant adeno-associated vectors (AAV) are the vectors of choice for liver gene transfer and have recently achieved remarkable successes in clinical trials. However, there are still large groups of patients who have limited access to therapy.

Challenges in AAV-Mediated Liver Gene Therapy

The major hurdles toward expanding the indication of AAV-mediated liver gene therapy are:

1. Transient AAV-Mediated Expression: This occurs in proliferating hepatocytes, such as in newborn or regenerating livers, due to the dilution of the episomal AAV genome in proliferating cells.
2. Dose-Dependent Hepatotoxicity: There is an immune response against AAVs that can limit their effectiveness.
3. Pre-Existing Immunity: Approximately 50% of individuals have pre-existing immunity to AAV capsids, which currently precludes systemic delivery.

AAVolution's Objectives

AAVolution gathers renowned European experts in the field of AAV vectorology, gene therapy, genome editing, and immunology, with the ambitious goal to develop and implement innovative therapeutic tools to effectively address these challenges. To this aim, AAVolution proposes:

1. Novel Small Cas Nucleases: To seek novel small Cas nucleases for in vivo AAV-mediated genome editing.
2. Self-Replicating Episomal AAVs: To develop self-replicating episomal AAVs to avoid transgene dilution in proliferating livers.
3. Synthetic AAVs: To generate synthetic AAVs characterized by enhanced potency and reduced toxicity, by screening novel AAV capsid libraries.
4. Improved Technologies: To develop improved technologies to overcome pre-existing immunity to AAVs by transiently reducing the levels of circulating anti-AAV neutralizing antibodies.

Impact of AAVolution

AAVolution will significantly expand the toolkit for AAV-mediated liver gene therapy, developing novel and improved molecular instruments to address the most relevant hurdles toward safer and more effective therapies. This initiative aims to provide access to treatment for patients that are currently excluded from clinical trials.

Moreover, these novel tools will constitute an innovative platform with the potential for broad expansion of disease indications beyond rare diseases.