WP4 will develop a multidimensional approach to achieve effective delivery of different types of reagents to the intended target cell/tissue. We will develop nanoparticles to deliver CRISPR systems. Lipo-oligomers will be formulated and VSV-G enveloped vesicles (Vesicas) to carry Cas9/sgRNA ribonucleoprotein complexes (RNPs).
Specific particles will be developed to target muscle (WP6), retina (WP8), and liver (WP9) using tissue specific splice-modulating sequences and tissue specific targeting. We will combine vesicas with lipo-oligomers shielding to increase vesicle stability and targeting. We will also broaden the tropism of lentiviral vectors by advanced pseudotyping using metagenomics barcoded envelope libraries screened in vivo.
Specific WP’s objectives:
- Retarget tropism of lentiviral vectors by surface modification
- Design non-viral gene and genome modifier formulations and select in vivo delivery route to maximize efficacy and target tropism at reduced toxicity
- Task 4.1: Advanced LV pseudotyping in vivo for tissue retargeting
- Task 4.2: Optimization of the VSV-G enveloped vesicles (VEsiCas) system
- Task 4.3: Develop and provide sequence-defined synthetic carriers for in vivo applications
- Task 4.4: Development of improved lipoplexes formulations for in vivo delivery of Cas9/sgRNA RNP
- Task 4.5: Improved non-viral intranuclear delivery of donor DNA
- Task 4.6: Non-viral receptor-targeted Cas9/sgRNA formulation for selected organs/diseases
WP leader: Ernst Wagner (LMU)
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