Next-generation AAV vectors for liver-directed gene therapy

Project Information

AAVolution

Grant agreement ID: 101071041

DOI

10.3030/101071041

EC signature date 11 July 2022

Start date 1 October 2022

End date 30 September 2027

Funded under

• The European Innovation Council (EIC)

Total cost

€ 4 500 000,00

EU contribution

€ 4 500 000,00

Coordinated by

FONDAZIONE TELETHON ETS
Italy

Periodic Reporting for period 1 - AAVolution (Next-generation AAV vectors for liver-directed gene therapy)

Reporting period: 2022-10-01 to 2023-09-30

Summary of the context and overall objectives of the project

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.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

In the first project report, the AAVolution team achieved significant advancements in improving AAV vectors for liver gene therapy. As for the approach of gene editing and long-term effects (WP1), we found a promising Cas9 variant to be integrated into AAV vectors, which is effective for gene editing and is currently being tested in living organisms. We also explored ways to make the therapy last longer by investigating units that can autonomously replicate and maintain gene expression.
In addition, regarding the studies on AAV capsids (the carrier of therapeutic genes) (WP2), we created diverse libraries of AAV capsids to find the best ones for effective treatment. We used advanced techniques, including DNA shuffling and rational design, resulting in over 3000 variants. These variants underwent rigorous checks to ensure their quality.
In addressing pre-existing immune response challenges (WP3), we also generated important results. Through innovative approaches, we discovered 48 new Ide molecules, which hold promise in reducing immune responses to the therapy, and developed a machine learning flexible pipeline for designing more Ide. This is crucial for reducing immune responses against AAV therapy.
Overall, the AAVolution team is working to improve liver gene therapy better by using more effective gene-editing tools, exploring ways to make the therapy last longer, and creating diverse libraries of carriers for therapeutic genes. Additionally, the project is also addressing challenges related to the body's immune response to the therapy. These advancements bring hope for more effective and accessible gene therapies in the future.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

In the first project report, the AAVolution Project Management Team successfully coordinated various aspects, from organizing key meetings to communicating with the EU officers. We particularly emphasized managing intellectual property and devised a plan to safeguard AAVolution’s innovations.
In the strategic planning and regulatory engagement aspects, we submitted a comprehensive Cell and Gene Therapy (CGT) Strategic Plan, outlining objectives and collaborations with other projects. We also actively engaged with regulatory authorities through participation in an EMA webinar and maintained continuous interaction with private investors, showcasing their project in the EIC CGT Symposium.