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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - IMGENE (Improving Genome Editing Efficiency (IMGENE))

Teaser

Summary

CRISPR genome editing is a novel breakthrough technology that revolutionized biomedical and pharmaceutical research and opened up new avenues for the therapy of genetic diseases. In short, CRISPR genome editing allows to cleave genomic DNA at a specific location, which then triggers the deletion, replacement or introduction of DNA depending on the experimental conditions. Different DNA repair pathways are involved of which the homology-directed repair (HDR) is allowing specific DNA replacements and defined changes, while the non-homologous end joining (NHEJ) repair is causing various mutations around the repair site. For gene therapy and many research questions, it would be ideal if all repair would be carried out by HDR. Under current experimental conditions, however, NHEJ is the prevalent repair method, which is a major obstacle for many potential applications of CRISPR genome editing. The IMGENE consortium consisting of 6 European research institutions, 1 pharmaceutical company, two associated industrial partners and a patient organization representing people suffering from genetic diseases, is aiming to find ways to improve HDR efficiency of CRISPR genome editing.

Work performed

This is performed by optimizing the DNA cutting CRISPR nuclease called Cas9, by increasing the transport of CRISPR/Cas9 nuclease and donor DNA into the target cells, and by finding small molecular weight substances that promote HDR and inhibit NHEJ. In addition, one research project is addressing the complex ethical issues related to CRISPR/Cas9 mediated genome editing of animals, and humans. Eight PhD students have been recruited working on these tasks and managed already to generate variants of the Cas9 nuclease and to identify inhibitors that increase the HDR to NHEJ ratio during CRISPR genome editing. Furthermore, different viral vector systems and electroporation have been employed to promote the transport of CRISPR tools into the nucleus of the target cells. These preliminary results are now validated, including in some cases their application for the repair of disease-causing genetic mutations in cell lines and mice. The vision is to add all validated improvements into a new protocol for CRISPR genome editing by HDR.

Final results

Finally, IMGENE is trying to contribute to an informed discussion of this technology in the context of responsible research and innovation by mapping views and expectations of CRISPR experts on the applications and risks of this technology. As CRISPR genome editing is used world-wide in countries with rather diverse cultural backgrounds, this study is also involving stakeholders in Brazil, North America, and China, in addition to Europe.
The IMGENE consortium furthermore provides a special training of the PhD students in transferable skills, intellectual property rights, and entrepreneurship that increases their chances to become leaders in their field and to promote the development of a ethically correct genome editing industry in Europe.