Periodic Reporting for period 1 - iAds (Intelligent design of adenovirus vectors (iAds))
Reporting period: 2023-05-01 to 2024-04-30
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 and Swedish 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 adenoviruses. Instead, a novel adenovirus type 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.
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 and Swedish 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 adenoviruses. Instead, a novel adenovirus type 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.
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.
The in silico design led to the proposal of ~25 constructs that will be tested for their ability to produce vectors. This initial “moonshot” where we attempted the most radical design is being screened for viability.
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.
The in silico design led to the proposal of ~25 constructs that will be tested for their ability to produce vectors. This initial “moonshot” where we attempted the most radical design is being screened for viability.
After only 12 months, it is premature to address this criterion.