The delivery challenge: fulfilling the promise of therapeutic genome editing
Top Cited Papers
Open Access
- 1 July 2020
- journal article
- review article
- Published by Springer Science and Business Media LLC in Nature Biotechnology
- Vol. 38 (7), 845-855
- https://doi.org/10.1038/s41587-020-0565-5
Abstract
As CRISPR therapies move into clinical testing, David Schaffer and colleagues review a raft of different delivery technologies being road tested to address cargo capacity limitations, maximize potency, minimize off-target effects and avoid immunogenicity. Genome editing has the potential to treat an extensive range of incurable monogenic and complex diseases. In particular, advances in sequence-specific nuclease technologies have dramatically accelerated the development of therapeutic genome editing strategies that are based on either the knockout of disease-causing genes or the repair of endogenous mutated genes. These technologies are progressing into human clinical trials. However, challenges remain before the therapeutic potential of genome editing can be fully realized. Delivery technologies that have serendipitously been developed over the past couple decades in the protein and nucleic acid delivery fields have been crucial to genome editing success to date, including adeno-associated viral and lentiviral vectors for gene therapy and lipid nanoparticle and other non-viral vectors for nucleic acid and protein delivery. However, the efficiency and tissue targeting capabilities of these vehicles must be further improved. In addition, the genome editing enzymes themselves need to be optimized, and challenges regarding their editing efficiency, specificity and immunogenicity must be addressed. Emerging protein engineering and synthetic chemistry approaches can offer solutions and enable the development of safe and efficacious clinical genome editing.Funding Information
- National Science Foundation (Graduate Fellowship)
- U.S. Department of Health & Human Services | National Institutes of Health (RO1EB023776, UG3NS115599)
- Innovative Genomics Institute
- Gilbert Family Foundation, Chan Zuckerberg Biohub, Innovative Genomics Institute
This publication has 132 references indexed in Scilit:
- A Programmable Dual-RNA–Guided DNA Endonuclease in Adaptive Bacterial ImmunityScience, 2012
- Targeted gene knockout by direct delivery of zinc-finger nuclease proteinsNature Methods, 2012
- Intracellular DNA recognitionNature Reviews Immunology, 2010
- Lipid-like materials for low-dose, in vivo gene silencingProceedings of the National Academy of Sciences of the United States of America, 2010
- Effect of Genome Size on AAV Vector PackagingMolecular Therapy, 2010
- Safety and Efficacy of Gene Transfer for Leber's Congenital AmaurosisThe New England Journal of Medicine, 2008
- Efficacy and safety of adeno‐associated viral vectors based on serotype 8 and 9 vs. lentiviral vectors for hemophilia B gene therapyJournal of Thrombosis and Haemostasis, 2006
- LMO2 -Associated Clonal T Cell Proliferation in Two Patients after Gene Therapy for SCID-X1Science, 2003
- In Vivo Gene Delivery and Stable Transduction of Nondividing Cells by a Lentiviral VectorScience, 1996
- Cloning and sequence analysis of cDNA for human prealbuminBiochemical and Biophysical Research Communications, 1984