Over the last decade, CRISPR/Cas9-based techniques have been developed for various genomic engineering strategies in eukaryotic cells. Using single guide RNAs (sgRNA) containing specific targeting sequences, Cas9 can target precise genomic locations. Here, Cas9 can be employed to create double-stranded DNA breaks, generate precise mutations, incorporate specific sequences, or regulate RNA transcription. Thus, CRISPR/Cas9-based techniques are of substantial interest for the development of novel therapies to treat genetic diseases. Moreover, as they can be targeted to precise genomic targets with high specificity, they have considerable therapeutic potential for currently “un-druggable” pathologies. Unfortunately, one of the major hurdles in the development of CRISPR/Cas9-based therapies is the intracellular delivery of Cas9-sgRNA complexes. Cas9-sgRNA complexes are unable to cross the cell membrane due to their large size, as well as their negative charge. Moreover, Cas9-sgRNA complexes need to be shielded from opsonization and degradation in circulation, due to their immunogenicity.
To address these problems, your project will focus on the development of extracellular vesicle (EV)-mediated strategies for CRISPR/Cas9 delivery. EVs are lipid membrane nanovesicles released by cells that play an important role in intercellular communication. EVs hold considerable potential for delivery of biotherapeutics, due to their remarkable intrinsic capability of intercellular RNA and protein transfer, as well as their low immunogenicity and their potential for targeted tissue delivery. To harness EVs for CRISPR/Cas9 delivery, you will focus on the development of new strategies that facilitate targeted EV cargo loading and delivery. Techniques that the PhD candidate will employ include EV isolation techniques, CRISPR/Cas-based activity (including genetic engineering and transcriptional activation), the design and cloning of fusion proteins, and cell-based assays and analysis.
You will take part in the PhD program Drug Innovation of the Graduate School of Life Sciences , which will give you the opportunity to connect with other PhD students in your field and to follow courses.
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