Descrizione del progetto
Nuovi vettori adeno-associati per il trasferimento di geni epatici
I vettori ricombinanti adeno-associati (AAV) hanno ottenuto un notevole successo nelle recenti sperimentazioni cliniche per il trasferimento di geni epatici. Diversi ostacoli impediscono tuttavia l’espansione della terapia mediata da AAV a tutti i pazienti, tra cui l’espressione transitoria mediata da AAV negli epatociti proliferanti a causa della diluizione episomale del genoma AAV, l’epatotossicità e la risposta immunitaria contro gli AAV e l’immunità preesistente ai capsidi AAV. Il progetto AAVolution, finanziato dall’UE, propone di trovare nuove piccole nucleasi Cas per l’editing del genoma mediato da AAV in vivo con AAV episomali autoreplicanti. L’obiettivo è evitare la diluizione dei transgeni, creare AAV sintetici con una tossicità ridotta e sviluppare tecnologie per superare l’immunità preesistente agli AAV. Il nuovo set di strumenti consentirà un’ampia espansione della terapia genica mediata da AAV per indicazioni che vanno oltre le malattie rare.
Obiettivo
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.
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, and provide access to treatment to 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 the rare diseases.
Campo scientifico
Parole chiave
Programma(i)
- HORIZON.3.1 - The European Innovation Council (EIC) Main Programme
Argomento(i)
Invito a presentare proposte
HORIZON-EIC-2021-PATHFINDERCHALLENGES-01
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HORIZON-EIC - HORIZON EIC GrantsCoordinatore
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