Stem cell-derived clade F AAVs mediate high-efficiency homologous recombination-based genome editing

Abstract

Significance Precise genomic correction of pathogenic mutations is an attractive therapeutic strategy. Here, we show that a unique class of stem cell-derived nonpathogenic virus, hematopoietic stem cell-derived adeno-associated virus vector (AAVHSC), mediates precise genome editing at unprecedented efficiencies in primary human cells, including postmitotic cells, and in vivo. Unlike the majority of current editing platforms, genome editing by AAVHSC is uniquely based on homologous recombination (HR), requiring no exogenous nucleases. AAVHSC-mediated editing is seamless, with no evidence of on-target insertion/deletion mutations common to nuclease-based platforms. Efficient in vivo editing was achieved by i.v. injection of AAVHSC editing vectors. The combination of efficient and precise HR-based genome editing coupled with the superior in vivo transduction properties of AAV facilitates progress toward in vivo therapeutic gene editing.