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 in proliferating hepatocytes, i.e., newborn or regenerating livers, due to dilution of episomal AAV genome in proliferating cells.
2. Dose-dependent hepatotoxicity and immune response against AAVs.
3. Pre-existing immunity to AAV capsids, which currently precludes its systemic delivery in about 50% of individuals.

AAVolution's Goals

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. To seek novel small Cas nucleases for in vivo AAV-mediated genome editing.
2. To develop self-replicating episomal AAVs to avoid transgene dilution in proliferating livers.
3. To generate synthetic AAVs characterized by enhanced potency and reduced toxicity, by screening of novel AAV capsid libraries.
4. 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 a potential for broad expansion of disease indications beyond rare diseases.