Engineered virus-like particles for transient delivery of prime editor ribonucleoprotein complexes in vivo.

Autor: An M; Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.; Howard Hughes Medical Institute, Harvard University, Cambridge, MA, USA., Raguram A; Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.; Howard Hughes Medical Institute, Harvard University, Cambridge, MA, USA., Du SW; Gavin Herbert Eye Institute, Center for Translational Vision Research, Department of Ophthalmology, University of California, Irvine, CA, USA.; Department of Physiology and Biophysics, University of California, Irvine, CA, USA., Banskota S; Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.; Howard Hughes Medical Institute, Harvard University, Cambridge, MA, USA., Davis JR; Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.; Howard Hughes Medical Institute, Harvard University, Cambridge, MA, USA., Newby GA; Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.; Howard Hughes Medical Institute, Harvard University, Cambridge, MA, USA., Chen PZ; Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.; Howard Hughes Medical Institute, Harvard University, Cambridge, MA, USA., Palczewski K; Gavin Herbert Eye Institute, Center for Translational Vision Research, Department of Ophthalmology, University of California, Irvine, CA, USA.; Department of Physiology and Biophysics, University of California, Irvine, CA, USA.; Department of Chemistry, University of California, Irvine, CA, USA.; Department of Molecular Biology and Biochemistry, University of California, Irvine, CA, USA., Liu DR; Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of MIT and Harvard, Cambridge, MA, USA. drliu@fas.harvard.edu.; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA. drliu@fas.harvard.edu.; Howard Hughes Medical Institute, Harvard University, Cambridge, MA, USA. drliu@fas.harvard.edu.
Jazyk: angličtina
Zdroj: Nature biotechnology [Nat Biotechnol] 2024 Oct; Vol. 42 (10), pp. 1526-1537. Date of Electronic Publication: 2024 Jan 08.
DOI: 10.1038/s41587-023-02078-y
Abstrakt: Prime editing enables precise installation of genomic substitutions, insertions and deletions in living systems. Efficient in vitro and in vivo delivery of prime editing components, however, remains a challenge. Here we report prime editor engineered virus-like particles (PE-eVLPs) that deliver prime editor proteins, prime editing guide RNAs and nicking single guide RNAs as transient ribonucleoprotein complexes. We systematically engineered v3 and v3b PE-eVLPs with 65- to 170-fold higher editing efficiency in human cells compared to a PE-eVLP construct based on our previously reported base editor eVLP architecture. In two mouse models of genetic blindness, single injections of v3 PE-eVLPs resulted in therapeutically relevant levels of prime editing in the retina, protein expression restoration and partial visual function rescue. Optimized PE-eVLPs support transient in vivo delivery of prime editor ribonucleoproteins, enhancing the potential safety of prime editing by reducing off-target editing and obviating the possibility of oncogenic transgene integration.
(© 2024. The Author(s).)
Databáze: MEDLINE
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