Intelligent design of adenovirus vectors (iAds)

Project Information

iAds

Grant agreement ID: 101098647

DOI

10.3030/101098647

EC signature date 20 December 2022

Start date 1 May 2023

End date 30 April 2027

Funded under

• The European Innovation Council (EIC)

Total cost

€ 3 959 506,68

EU contribution

€ 3 959 506,68

Coordinated by

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
France

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

Reporting period: 2024-05-01 to 2025-10-31

Summary of the context and overall objectives of the project

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.

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

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.

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)

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.