Next-generation AAV vectors for liver-directed gene therapy

Informazioni relative al progetto

AAVolution

ID dell’accordo di sovvenzione: 101071041

DOI

10.3030/101071041

Data della firma CE 11 Luglio 2022

Data di avvio 1 Ottobre 2022

Data di completamento 30 Settembre 2027

Finanziato da

• The European Innovation Council (EIC)

Costo totale

€ 4 500 000,00

Contributo UE

€ 4 500 000,00

Coordinato da

FONDAZIONE TELETHON ETS
Italy

Periodic Reporting for period 2 - AAVolution (Next-generation AAV vectors for liver-directed gene therapy)

Periodo di rendicontazione: 2023-10-01 al 2025-03-31

Sintesi del contesto e degli obiettivi generali del progetto

Over the past 20 years, scientists have made significant progress in a special kind of treatment for rare genetic diseases called liver-directed gene therapy, where viral-based carriers (AAVs) are used to deliver therapeutic genes to the liver. While this treatment has shown success in clinical trials, many patients still can't access it. The challenges include the temporary nature of the treatment in growing livers (newborns and children), potential side effects, and pre-existing immunity in some individuals. To tackle these issues, the AAVolution consortium has come together with the ambitious goal of developing new tools to enhance liver gene therapy. The strategy includes finding better tools for gene editing, creating self-replicating AAVs to make the treatment last longer, and designing safer synthetic AAVs. The ultimate aim is to significantly expand the toolkit for liver gene therapy, making it safer and more effective, thus helping patients who are currently excluded from these treatments due to immune issues, liver problems, or being too young. The project also envisions going beyond rare diseases and making this treatment available for a broader range of disease conditions.
Overall, the AAVolution team is focused on making liver gene therapy better and accessible to more people, potentially changing lives and opening up new possibilities in medicine.

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

In the second reporting period, AAVolution also strengthened its activities beyond the core scientific objectives through effective coordination, communication, and portfolio engagement. The consortium maintained transparent and efficient project governance, achieved key communication milestones including updated promotional materials and the successful organisation of the Second Annual Meeting, and submitted a revised Data Management Plan reinforcing its commitment to open science, FAIR data principles, and Horizon Europe compliance. At the same time, the project management team continued monitoring the implementation of the IP and Exploitation Plan, while the Technology Transfer Office actively worked with partners to identify and support protectable results. At portfolio level, AAVolution further consolidated its strategic role within the EIC Cell and Gene Therapy Portfolio by contributing to joint planning, participating in strategic meetings, and confirming its role as organiser of the 2026 Annual Portfolio Meeting in Pozzuoli, Italy. The project also engaged with key regulatory and industrial stakeholders through EMA- and FDA-related webinars, interactions with manufacturing and commercialization experts, and exchanges with initiatives such as the Novo Nordisk Foundation’s Cellerator programme. These activities strengthened AAVolution’s regulatory preparedness, visibility, translational positioning, and integration within the broader European cell and gene therapy innovation ecosystem.

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

During the second reporting period, AAVolution achieved significant progress beyond the state of the art in liver-directed gene therapy by addressing key limitations related to delivery efficiency, durability of expression, and immune barriers.
The project expanded genome editing possibilities by identifying and optimising novel compact RNA-guided nucleases, enabling more efficient delivery within viral vectors. In parallel, new AAV capsid variants were developed and validated in preclinical models, showing improved liver targeting and transduction efficiency compared to existing vectors, including in fibrotic conditions. Innovative “armoured” AAV vectors were also generated to enhance tissue penetration.
To address the challenge of transient expression, novel vector designs demonstrated the potential to sustain transgene expression over time in proliferating cells. In addition, AAVolution developed new strategies to overcome pre-existing immunity, including the identification of highly active IgG-degrading enzymes and the evaluation of clinically relevant immunomodulatory approaches.
These results support future translation by enabling more effective and accessible gene therapies. Further steps will focus on preclinical validation, regulatory alignment, protection of intellectual property, and engagement with industrial and financial stakeholders to support scale-up and clinical development.