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

Proceedings of the National Academy of Sciences of the United States of America
Laura J SmithSaswati Chatterjee

Abstract

The precise correction of genetic mutations at the nucleotide level is an attractive permanent therapeutic strategy for human disease. However, despite significant progress, challenges to efficient and accurate genome editing persist. Here, we report a genome editing platform based upon a class of hematopoietic stem cell (HSC)-derived clade F adeno-associated virus (AAV), which does not require prior nuclease-mediated DNA breaks and functions exclusively through BRCA2-dependent homologous recombination. Genome editing is guided by complementary homology arms and is highly accurate and seamless, with no evidence of on-target mutations, including insertion/deletions or inclusion of AAV inverted terminal repeats. Efficient genome editing was demonstrated at different loci within the human genome, including a safe harbor locus, AAVS1, and the therapeutically relevant IL2RG gene, and at the murine Rosa26 locus. HSC-derived AAV vector (AAVHSC)-mediated genome editing was robust in primary human cells, including CD34+ cells, adult liver, hepatic endothelial cells, and myocytes. Importantly, high-efficiency gene editing was achieved in vivo upon a single i.v. injection of AAVHSC editing vectors in mice. Thus, clade F AAV-mediated genom...Continue Reading

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Citations

Feb 8, 2019·Laboratory Investigation; a Journal of Technical Methods and Pathology·Noboru IdenoBidyut Ghosh
Jul 28, 2019·Human Gene Therapy·Nerea ZabaletaGloria Gonzalez-Aseguinolaza
Feb 3, 2019·Nature Reviews. Drug Discovery·Dan WangGuangping Gao
Apr 8, 2020·Molecular Therapy. Methods & Clinical Development·Seemin S AhmedOmar L Francone
Jun 19, 2021·Signal Transduction and Targeted Therapy·Hong-Yan ZhaoXiao-Jun Huang
Sep 13, 2021·Molecular Therapy : the Journal of the American Society of Gene Therapy·Byung-Chul LeeCynthia E Dunbar

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