WP5 will characterize and then develop strategies to reduce innate and adaptive immune responses to the gene transfer and editing components, some of which are of prokaryotic origin. Particular efforts will be made to tackle pre-existing cellular immunity agaist AAV capsisds and targeted tolerogenic strategies will be tested in immune humanised rodent models and NHP.
We will also modulate the surface composition of LV and vesicles to reduce phagocytosis by professional APCs, forcing expression of phagocytosis inhibitors (CD47, PDL-1) and/or decreasing expression of pro-phagocytic signals (calreticulin, SFR) in LV producer cells, and further decreasing interaction with complement by co-administration of complement blocking antibodies.
Specific WP’s objectives:
- Evaluate and modulate human pre-existing Cas9 immunity and immunogenicity in animal models
- Evaluate human pre-existing anti-AAV immunity and immunogenicity in animal models
- Modulate anti-AAV/anti-Cas9 cellular immunity using targeted tolerogenic strategies
- Generate novel phagocytosis-resistant immune stealth LV
- Reduced immunogenicity of Cas9/sgRNP delivery via nonantigenic anti-inflammatory carriers
Tasks:
- Task 5.1: Characterization of pre-existing anti-AAV cellular immunity in humans and its impact on AAV-mediated gene transfer
- Task 5.2: Development of targeted tolerogenic strategies aiming at anti-AAV cellular immunity modulation
- Task 5.3: Generation of novel phagocytosis-resistant immune stealth LV
- Task 5.4: Characterization and modulation of immunity towards Cas9 protein variants
- Task 5.5: Reduced immunogenicity of Cas9/sgRNP delivery via nonantigenic anti-inflammatory carriers
Timeline:
WP leader: Oumeya Adjali (UNNANTES)
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