BACKGROUND
Rapid progress in the genome editing field is contributing to solving complex scientific questions and to develop advanced gene and cell therapies for tackling genetic disorders with unmet medical needs and high societal burdens. Yet, critical improvements at the levels of gene-editing tool delivery and precision are in demand. The Genome editing group at the Department of Cell and Chemical Biology of the LUMC focuses its research on these two critical aspects by investigating; (i) viral vectors as delivery agents of gene-editing tools; and (ii) seamless gene-editing strategies which, in contrast to conventional approaches, do not generate mutagenic double-stranded breaks at chromosomal sequences. The resulting findings and toolboxes are starting to be directed towards the modeling and correction of genetic disorders. These interconnected research lines seek to contribute to the treatment of monogenetic disorders of the striated musculature and hematopoietic system and, to this end, include collaborations with colleagues from the LUMC, other Dutch institutions and European networks. Important portions of our research builds upon the pioneering role of the Leiden University and the LUMC on adenoviral vector research, hematopoietic stem cell transplantation and Duchenne muscular dystrophy.
RESEARCH
We investigate new genome editing principles based on the activation and guiding of specific DNA repair processes after the delivery of gene editing tools into target cells. Gene editing tools under investigation include programmable DNA-cleaving enzymes (nucleases and “nickases”) and exogenous DNA-repairing templates (donor DNA). We further study the genome editing outcomes (wanted and unwanted) resulting from using nucleases versus “nickases” and donor DNA substrates with different structures and topologies. This research seeks to achieve seamless and scarless chromosomal DNA editing for modeling or repairing genetic defects in pluripotent stem cells and tissue-specific stem/progenitor cells. Underpinning these investigations, we develop and integrate gene delivery and gene editing technologies grounded on recombinant viruses and programmable nucleases, e.g., adenoviral vectors and CRISPR systems, respectively.
Additional information about our team and research activities is available via the links:
- Francesca Tasca (Marie Skłodowska-Curie Ph.D. fellow) winner of the Annual Prize for Neuromuscular Diseases 2022 - Best scientific article Francesca Tasca wint Jaarprijs 2022 - Spierfonds
- Active Horizon Europe Doctoral Network GETRADI - "Gene Therapy of Rare Diseases" Getradi – University of Copenhagen (ku.dk)
- Collaborative Dutch Research Council (NWO) - Open Technology Programme research project HARVEY – Prof. P. Doevendans (UMCU), Dr. G. Boink (AUMC) and Dr. Gonçalves (LUMC) Financiering voor "Harvey"! - PLN Foundation (plnheart.org)
- Collaborative Prinses Beatrix Spierfonds research project on DMD gene repair –Dr. M. Gonçalves and Prof. Annemieke Aartsma-Rus “Duchenne-patiënten verdienen een therapie” - Spierfonds
Concluded Horizon 2020 European Training Network IMGENE – “Improving Genome Editing Efficiency” https://imgene.ku.dk/about-imgene/
Muscling out gene mutations | Science Translational Medicine
- Why Viruses may be a Genome Editor's Secret Weapon | Discover Magazine
- BioInsights - Trends and advances in gene therapy delivery and gene editing - spotlight
Adenoviral Delivery of CRISPR/Cas9 Aims to Expand Genome Editing to Primary Cells (addgene.org)
Testimonial Manuel Gonçalves, associate professor | LUMC
PhD theses from lab alumni:
- Maarten Holkers "The roles of adenoviral vectors and donor DNA structures on genome editing" (2016) https://openaccess.leidenuniv.nl/handle/1887/37412.
- Current position, Associate Director at ProQR Therapeutics, Leiden, the Netherlands.
- Ignazio Maggio (cum laude) "Adenoviral vectors as genome editing tools: repairing defective DMD alleles" (2016) https://openaccess.leidenuniv.nl/handle/1887/44288.
- LUMC Best Thesis Prize 2017 (Non-clinical).
- Greiner Award 2017 from the Netherlands Society of Gene and Cell Therapy for the best thesis in the field of Gene Therapy carried out at a Dutch University or Institute.
- Current position, Lecturer, Free University Amsterdam, Center for Neurogenomics and Cognitive Research.
- Xiaoyu Chen "Determinants of genome editing outcomes: the impact of target and donor DNA structures" (2018) https://openaccess.leidenuniv.nl/handle/1887/62204.
- Current position, Postdoctoral fellow, Stanford University, Dep. of Psychiatry and Behavioral Sciences, USA.
