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.
Fields of science
- medical and health sciencesbasic medicinepharmacology and pharmacydrug safety
- medical and health sciencesmedical biotechnologygenetic engineeringgene therapy
- medical and health sciencesbasic medicineimmunology
- natural sciencesbiological sciencesgeneticsgenomes
- medical and health sciencesmedical biotechnologycells technologies
Keywords
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Funding Scheme
RIA - Research and Innovation actionCoordinator
S10 2TN Sheffield
United Kingdom
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Participants (33)
08014 Barcelona
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75015 PARIS 15
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3004 517 Coimbra
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91002 Evry
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91000 EVRY
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The organization defined itself as SME (small and medium-sized enterprise) at the time the Grant Agreement was signed.
2781-901 Oeiras
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The organization defined itself as SME (small and medium-sized enterprise) at the time the Grant Agreement was signed.
75013 Paris
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75654 Paris
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22100 Lund
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92200 Neuilly Sur Seine
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The organization defined itself as SME (small and medium-sized enterprise) at the time the Grant Agreement was signed.
30625 Hannover
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2342 DH Oegstgeest
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The organization defined itself as SME (small and medium-sized enterprise) at the time the Grant Agreement was signed.
6726 Szeged
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The organization defined itself as SME (small and medium-sized enterprise) at the time the Grant Agreement was signed.
6971039 Tel Aviv
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The organization defined itself as SME (small and medium-sized enterprise) at the time the Grant Agreement was signed.
00128 Roma
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The organization defined itself as SME (small and medium-sized enterprise) at the time the Grant Agreement was signed.
CB2 1TN Cambridge
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OX11 0QX Didcot
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L69 7ZX Liverpool
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69120 Heidelberg
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WC1E 6BT London
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70211 KUOPIO
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OX1 2JD Oxford
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CT13 9NJ Sandwich
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51373 Leverkusen
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2340 Beerse
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4002 Basel
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4056 Basel
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2880 Bagsvaerd
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94250 GENTILLY
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19808 Wilmington
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8152 Glattpark
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31192 ARANGUREN
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2333 BE Leiden
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