About the research
The first target group of the project is composed patients with indications where genome editing. Only SCD affects more than 330,000 newborns worldwide each year (being the most common monogenic disease worldwide) and a large scientific community aims at understanding the mechanisms underlying the complex SCD pathophysiology to find potential therapeutic options, the results of this project will have widespread positive and beneficial outcomes and impacts. Furthermore, the results and technical outputs of this project will be primarily employed by the scientific academic and industrial research communities where EdiGenT will facilitate advances in the development of effective, must-have cell and gene editing products. This will be achieved by providing these groups with optimized and standardized methodologies in genome editing. Healthcare providers will be direct beneficiaries of improved genome editing products. Pharma Industry and Venture Capital funders are also target groups of this project. For example, as potential clinical applications become apparent during the course of our research, we will establish proper industrial partnerships to fully exploit the potential of our results. Importantly, patients, their families, patient organizations, general public and high school students will be engaged to disseminate knowledge on SCD and its innovative, genome editing-based treatments. Regulators will also be engaged to explore the benefits of the tools and technologies developed as not only innovative therapies for unmet medical needs, but also best in class supporting, and enabling tools to facilitate the development of effective and safe genome editing products.
Scientific context: since their first report in the scientific literature CRISPR/Cas9-based technologies have impacted the possibility of genome editing with an extraordinary power. PE is nowadays the most powerful and promising genome editing tool offering an unmatched precision and flexibility of modifying eukaryotic genomes. As such, EdiGenT by aiming at building on these premises to generate new tools with unprecedented efficacy and target cell specificity will greatly impact the large scientific community comprising both academic and industrial researchers interested in genome editing at large.
EdiGenT is articulated in 5 research and innovation work packages (WP) and 3 other WPs dedicated to project management (WP7), communication, dissemination, and exploitation of the project results (WP6) and portfolio activities (WP8).
The work plan spans a period of 60 months. The WPs structure follows a technological development logic: design/in vitro => test in vivo => relevant disease models. In parallel, technology development of novel PE strategies and delivery methods are performed in parallel. The development activities will constantly benefit from inputs from the groups testing the technology to introduce the required modifications according to the collected results.
Each WP has been assigned to a work package leader (WPL), according to the partners’ specific competences and strengths.
WP1: Development of novel prime editing tools
WP2: Improvement of prime editing tools (zebrafish)
WP3: Nanoparticles for targeted delivery of PE RNPs
WP4: Targeted nanoparticle delivery in zebrafish
WP5: Testing optimized prime editing reagents in SCD patient-derived cells in vitro and in vivo
Development of novel prime editing tools
Improvment of prime editing tools (zebrafish)
Nanoparticles for targeted delivery of PE RNPs
Targeted nanoparticle delivery in zebrafish
Testing optimized prime editing reagents in SCD patient-derived cells in vitro and in vivo
Communication dissemination and exploitation of the project results
The technology developed in this project will provide novel gene editing approaches for gene therapy and for basic science across disciplines in modern molecular biology and biotechnology working with complex eukaryotic genomes in model organisms and where HDR-based approaches are not feasible. More in particular, studies performed in the first part of the project will provide the scientific community with a better understanding of DNA repair and how to modulate/exploit the cellular DNA repair machinery.
The second part of the project will provide important knowledge and new tools for tissue specific delivery of genome editing complexes of nucleic acids and proteins in any cell type and animal for which specific ligands or antibodies are available.
Studies performed in the final part of the project will provide the scientific community with potentially clinically applicable genome editing protocols for curing SCD patients that can be readily tested in pre-clinical studies.
Finally, we will provide the large scientific community using zebrafish as a model system for basic and translational biomedical research with a ready usable toolbox that will further expand the power of this model system in the coming years.
The proof-of-concept study performed in the final part of the project will result in the development of clinically relevant approaches for gene therapy of SCD. This will pave the way for the initiation of best-in-class phase I/II clinical studies for SCD aimed at reducing the disease burden. Importantly, this study will also aid the scientific community and healthcare providers in treating diseases other than SCD, eventually benefiting a large number of patients. In particular, technologies developed and validated in this project will help to improve the general efficacy of PE in HSPCs, the target cell population in gene therapy trials for hematopoietic and non-hematopoietic disorders.
In the longer term, EdiGenT results will impact the world of personalized precision medicine in multiple ways. For instance, it will provide a more efficient multiplex gene editing tool allowing to pursue the goal of developing universal CAR-T cells for cell-based therapies. At the same time, this approach applied to the zebrafish model system will allow the creation of personalized disease models for rare genetic disease but also for cancer-inducing somatic mutations. This technology will allow in turn the development of patient-specific drug screening for rapid drug repurposing results or to select the most effective therapeutic protocol when multiple candidates are available (as it is often the case of cancer therapy). The cell specific PE RNP nanoparticle targeting approach can be applied for other types of gene therapy approaches as a non-viral system, overcoming several problems linked to viral delivery when continuous gene expression is not required. As such this holds the potential to represent a non-toxic in vivo delivery of therapeutic cargo to specific cell types also for basic research studies.
In conclusion, the results of this project are expected to catalyze the development of novel strategies for the treatment of other genetic and non-genetic disorders and to have a general, positive impact on the development of the health technology and biotechnology community in Europe (target group: scientific community).