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Accelerating Research & Development for Advanced Therapies

Project description

Improving AAV gene therapy vector efficiency

Adeno-associated virus (AAV) is a non-enveloped virus that can be engineered to deliver DNA of interest to target cells for gene therapy purposes. However, pre-existing immunity renders AAV vectors inefficient as they get eliminated from the host. The EU-funded ARDAT project is bringing together experts in the field of gene therapy to fill the knowledge gaps regarding the immunogenicity of AAV vectors in gene therapy applications. Moreover, partners will study the metabolism of AAV gene therapy vectors, their degradation rate and their capacity to persist in episomal form. The long-term vision of ARDAT is to improve AAV vector efficiency in gene therapy trials.

Objective

Major current hurdles for wide clinical use of AAV vectors are attributable primarily to: (i) host elimination by both immune and non-immune sequestering mechanisms – such neutralization by host antibody responses critically limits the possibility of repeated AAV delivery; (ii) AAVs are prevalent in the environment and hence a large proportion of the population carry AAV antibodies (up to 80%)– this pre-existing immunity renders AAV unable to infect target cells forcing substantial patient cohorts to be excluded from clinical trials.
The current proposal is founded on compelling track record in the field and brings together a ‘best-with-best’ multidisciplinary team of international leading academic and EFPIA partners with complimentary expertise in gene therapy, immunology, chemistry, engineering, biotechnology, drug safety, viral vector production, regulatory and clinical trials. The overall goal is to analyse the currently available clinical data and then design preclinical and clinical studies to fill the knowledge gaps in advanced therapies development. Our main aims are to: 1) Develop improved model systems for predicting product immunogenicity in humans. This will be achieved by generating human and NHP 3D hepatic models; 2) Enhance our understanding of gene/cell therapy drug metabolism inside a host of cell types. The plan is to define metabolism of the therapeutic vector genome in different cell types to understand whether rates of degradation, episomal maintenance, or integration, and metabolic stress induced by AAV vector transgene expression vary from cell to cell. We will then adopt strategies to mitigate the loss of vector genomes and improve persistence; 3) Use diverse clinical expertise to establish the clinical factors around pre-existing immunity limiting patient access to advanced therapies therapy; 4) Engage regulators to ensure that the concepts and the data generated through this IMI programme will fill the gaps and support furture trials.

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Programme(s)

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Topic(s)

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Funding Scheme

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RIA - Research and Innovation action

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Call for proposal

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(opens in new window) H2020-JTI-IMI2-2019-18-two-stage

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Coordinator

THE UNIVERSITY OF SHEFFIELD
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 2 820 538,50
Address
FIRTH COURT WESTERN BANK
S10 2TN Sheffield
United Kingdom

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Region
Yorkshire and the Humber South Yorkshire Sheffield
Activity type
Higher or Secondary Education Establishments
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Total cost

The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.

€ 3 590 538,50

Participants (34)

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