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Generation of Novel Cardiotropic AAV-Based Serotypes to Evade Human Humoral Immunity

Generation of Novel Cardiotropic AAV-Based Serotypes to Evade Human Humoral Immunity

Objective

Cardiovascular diseases remain the primary cause of morbidity and mortality in the western countries. Pharmacological treatment improves survival and quality of life, but does not reverse disease progression. Gene therapy could fill this void, owing to its ability to treat the underlying cause. Adeno-associated viruses (AAV) emanated in the past decade as potent vectors, owing to their tropism for specific tissues, their low immunogenicity, their lack of pathogenicity and their ability to sustain long-term expression. As a testament to their potential, the European Commission approved the first gene therapy (Glybera) and several cardiac gene therapy clinical trials, one phase IIb, are underway using AAVs for gene targeting. Despite their growing success, a major impediment is the presence of pre-existing antibodies in patient serum, which excludes almost 50% of the population from clinical trials. The currently prominent approach, generation of novel serotypes from the known cardiotropic ones (AAV6 and 9) by random mutagenesis, alters favorable serotype attributes and most importantly tropism.
Our goal is to generate novel serotypes based on AAV6 and 9, using a directed mutagenesis approach, against only the amino acids involved in neutralization but not receptor binding and therefore tropism. The mutant AAVs will be tested in vitro and in vivo for neutralization, transduction efficiency and cardiac tropism. Alternatively, a semi-random mutagenesis library approach focusing on 3-5 key amino acids will be pursued.
Overall, the proposed study, using standard molecular biology techniques, will produce an immunogenic map of the cardiotropic AAVs, generate a panel of novel AAVs that evade humoral immunity but retain tropism, and therefore unequivocally provide with most needed vectors for human clinical trials and the opportunity for personalized medicine. Finally, this strategy will provide a proof of principle for other serotypes and diseases.
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Coordinator

UNIVERSITATSKLINIKUM HEIDELBERG

Address

Im Neuenheimer Feld 672
69120 Heidelberg

Germany

Activity type

Higher or Secondary Education Establishments

EU Contribution

€ 216 952,80

Administrative Contact

Thorsten Brietz (Mr.)

Project information

Grant agreement ID: 627329

Status

Closed project

  • Start date

    1 October 2014

  • End date

    30 September 2016

Funded under:

FP7-PEOPLE

  • Overall budget:

    € 216 952,80

  • EU contribution

    € 216 952,80

Coordinated by:

UNIVERSITATSKLINIKUM HEIDELBERG

Germany