Intelligent design of adenovirus vectors (iAds)

Informazioni relative al progetto

iAds

ID dell’accordo di sovvenzione: 101098647

DOI

10.3030/101098647

Data della firma CE 20 Dicembre 2022

Data di avvio 1 Maggio 2023

Data di completamento 30 Aprile 2027

Finanziato da

• The European Innovation Council (EIC)

Costo totale

€ 3 959 506,68

Contributo UE

€ 3 959 506,68

Coordinato da

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
France

Periodic Reporting for period 2 - iAds (Intelligent design of adenovirus vectors (iAds))

Periodo di rendicontazione: 2024-05-01 al 2025-10-31

Sintesi del contesto e degli obiettivi generali del progetto

Like many drugs, gene therapy is inherently linked to “delivery” efficacy. Over the last two decades, immense progress has been made in the development of viral vectors, which has identified characteristics and biological factors that reduce efficacy.
We propose an approach to overcome these limitations and construct a pathway for developing improved vectors for clinical gene transfer. By synergising French, Dutch, British, Spanish, Swedish, and Lithuanian expertise in structural biology, receptor engagement, neurobiology, and cardiobiology, we will create in silico-designed intelligent adenovirus vectors (iAds).
Our disruptive concept abandons the classical approach of developing vectors from naturally occurring adenovirus types. Instead, an adenovirus will be serially stripped of unwanted elements to create a bank of “iAd-Zeros”, which will then be engineered for heart- and brain-specific targeting. Our consortium blends academic ingenuity and SME/pharma manufacturing to allow seamless clinical translation. We hope to generate novel solutions in areas of unmet medical need via a platform that exploits the full potential of viral vectors.

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

The initial phase of iAds was to generate in silico designs of iAd-Zero, based on the permissible structural constraints, immunological parameters (induction of innate immune response and binding to extracellular proteins), and production potential. Modifications were proposed, 3D structures were generated and then screened for potential feasibility. The proposed modifications were based on screens of existing, as well as desired, characteristics.
To complement the in silico designs, we screen the starting material for its ability to interacts with antibodies, coagulation factors, and antimicrobial peptides. In addition, we documented its biodistribution following injection into the brain and its efficacy to transduce heart muscle cells in vitro. These data were overlaid on the structure-based analyses that identified capsid domains responsible for interacting with key cells surface molecules.
We found that a handful of iAd-Zero prototypes fulfilled many of our preset criteria.
Then, for our targeting approaches, we selected cell surface proteins and potential binding partners that were incorporated into the vector genome/external capsid. In vitro (cells and biochemical) and in vivo (rodents) assays have been used to screen our target capsids. These designs and functional assays will be reiterated throughout the duration of iAds to continually improve vector efficacy and functionality.

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)

Much of our early work is focused on the predictive values of machine learning-based (e.g. AlphaFold) design of individual adenovirus proteins. Not surprisingly, while some AlphaFold-inspired structures suggest a viable protein folding, they often did not produce viable capsid assembly.
The assembly of the 150 mDa adenovirus capsid, from cytoplasmic protein synthesis to transport to the nucleus for assembly, is a process that is still poorly understood. In this sense, our “failures” can be as informative as the successful generation of viable vectors. Our approach therefore accentuates the fundamentals of adenovirus biology as well as the potential for therapeutic use.

Project consortium at the iAds first annual meeting in April 2025 in Madrid

Partners awarding the students from Montpellier who won the iAds 1st Video contest in November 2024

Partners CSIC and UmU together at the 3rd Spanish Adeno meeting in February 2024 in Sevilla.

Project consortium at the iAds first annual meeting in April 2024 in Leiden.

Partners CSIC, BBS, UEDIN together 16th International Adenovirus Meeting in July 2025 in Cardiff.

Project consortium at the iAds kick-off meeting in April 2023 in Leiden.