Descripción del proyecto
Nuevos vectores adenoasociados para la transferencia de genes al hígado
Los vectores adenoasociados recombinantes (AAV, por sus siglas en inglés) han logrado un éxito notable en los últimos ensayos clínicos para la transferencia de genes al hígado. Sin embargo, varios obstáculos impiden la expansión de la terapia con AAV a todos los pacientes, como la expresión transitoria mediada por AAV en hepatocitos proliferantes debida a la dilución del genoma de AAV episomales, la hepatotoxicidad y la respuesta inmune contra los AAV, además de la inmunidad preexistente a las cápsides de AAV. El equipo del proyecto AAVolution, financiado con fondos europeos, se propone encontrar nuevas nucleasas Cas pequeñas para la edición del genoma mediada por AAV «in vivo» con AAV episomales autorreplicantes. El objetivo es evitar la dilución transgénica, crear AAV sintéticos con una toxicidad reducida y desarrollar tecnologías para superar la inmunidad preexistente a los AAV. El novedoso conjunto de herramientas permitirá una amplia expansión de la terapia génica mediada por AAV para indicaciones más allá de las enfermedades raras.
Objetivo
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.
Ámbito científico
Palabras clave
Programa(s)
- HORIZON.3.1 - The European Innovation Council (EIC) Main Programme
Tema(s)
Convocatoria de propuestas
HORIZON-EIC-2021-PATHFINDERCHALLENGES-01
Consulte otros proyectos de esta convocatoriaRégimen de financiación
HORIZON-EIC - HORIZON EIC GrantsCoordinador
00185 Roma
Italia