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Improving Genome Editing Efficiency (IMGENE)

Periodic Reporting for period 2 - IMGENE (Improving Genome Editing Efficiency (IMGENE))

Reporting period: 2019-09-01 to 2021-08-31

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.
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 to identify several small molecule inhibitors and to generate fusion proteins of Cas9 with DNA repair molecules which all increase HDR efficiency of CRISPR genome editing. Furthermore, adenoviral particles were prepared that effectively transduce dystrophin into myoblasts derived from Duchenne Muscular Dystrophy patients. In addition, a systematic review on “Public Genome Editing” on a basis of Pre-CRISPR vs Post-CRISPR comprising genetically modified animals and genetically modified humans was prepared. 9 scientific articles have already been published by the IMGENE consortium and at least 7 articles are currently prepared for submission.
The findings of IMGENE should now be applied to models for rare diseases, which are a group of more than 6000 genetic diseases affecting 300 million people worldwide. They also will be used to improve HDR-dependent genome editing in other research areas. In addition, the IMGENE projects initiated several other research projects in the partner institutions and contributed to a strengthened European network on improving CRISPR genome editing.
Finally, IMGENE contributed 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 provided 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 an ethically correct genome editing industry in Europe.