Master's internship proposal (M2)

Team: Immunology of gene transfer
Supervisor: Gwladys GERNOUX / Célia COUZINIE
gwladys.gernoux@univ-nantes.fr / celia.couzinie@univ-nantes.fr
Tel: +33 2 28 08 04 60

In vivo gene therapy using recombinant adeno-associated viral vectors (rAAV) has shown clinical benefits for the treatment of genetic disorders with 8 FDA- and EMA-approved drugs since 2012. These AAV vectors are now considered for correcting much more challenging acquired diseases with higher prevalence such as Alzheimer’s disease, age-related macular degeneration (AMD) or even cancer. However, there are still scientific bottlenecks to overcome for a successful clinical translation of such innovative biotherapies such as their immunogenicity in patients. Indeed, pre-existing anti-AAV humoral immunity can hinder gene therapy efficacy and induce safety concerns. This is a major challenge, particularly for clinical trials, since over 50% of patients present anti-AAV neutralizing antibodies (NAbs) depending on AAV serotypes and can be excluded from treatment eligibility.

Anti-AAV NAbs are typically detected using a cell-based transduction inhibition assay whereas anti-AAV total antibodies (TAbs) are detected by ELISA. However, protocols remain not standardized in the AAV gene therapy community. Over the past 15 years, our lab worked on the detection of both anti-AAV NAbs and TAbs and we have recently developed and validated a luminometric qualitative anti-AAV NAb assay using standardized controls according to regulatory guidelines such as EMA-ICH M10 and FDA guidelines for bioanalytical method validation guidance for industry.

During this internship, the candidate will have the opportunity to develop analytical methods to detect pre-existing anti-AAV NAbs and TAbs by screening healthy donors sera. The objectives will consist in i) extending the validation of the luminometric NAb assay to additional AAV serotypes and ii) develop quantitative assays to detect anti-AAV TAbs using ELISA and electrochemiluminescence.