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

Meirui AnAditya RaguramSamuel W DuSamagya BanskotaJessie R DavisGregory A NewbyPaul Z ChenKrzysztof PalczewskiDavid R Liu
Published in: Nature biotechnology (2024)
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.
Keyphrases
  • crispr cas
  • mouse model
  • risk assessment
  • gene expression
  • genome wide
  • blood brain barrier
  • ultrasound guided