| Project Detail |
Novel adeno-associated vectors for liver gene transfer
Recombinant adeno-associated vectors (AAV) achieved remarkable success in recent clinical trials for liver gene transfer. However, several hurdles prevent expansion of AAV-mediated therapy to all patients, including transient AAV-mediated expression in proliferating hepatocytes due to episomal AAV genome dilution, hepatotoxicity and immune response against AAVs, and pre-existing immunity to AAV capsids. The EU-funded AAVolution project proposes to find novel small Cas nucleases for in vivo AAV-mediated genome editing with self-replicating episomal AAVs. The aim is to avoid transgene dilution, create synthetic AAVs with reduced toxicity and develop technologies to overcome pre-existing immunity to AAVs. The novel tool set will enable broad expansion of AAV-mediated gene therapy for indications beyond rare diseases.
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. The major hurdles toward expanding the indication of AAV-mediated liver gene therapy are: i) transient AAV-mediated expression in proliferating hepatocytes, i.e. newborn or regenerating livers, due to dilution of episomal AAV genome in proliferating cells; ii) dose-dependent hepatotoxicity and immune response against AAVs; and iii) pre-existing immunity to AAV capsids, which currently preclude its systemic delivery in about 50% of individuals. 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: i) to seek novel small Cas nucleases for in vivo AAV-mediated genome editing ii)to develop self-replicating episomal AAVs to avoid transgene dilution in proliferating livers; iii) to generate synthetic AAVs characterized by enhanced potency and reduced toxicity, by screening of novel AAV capsid libraries; iv) and to develop improved technologies to overcome pre-existing immunity to AAVs by transiently reducing the levels of circulating anti-AAV neutralizing antibodies. |
