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Adenine Base Editing In Vivo with a Single Adeno-Associated Virus Vector.
14 auth. Han Zhang, Nathan Bamidele, Pengpeng Liu, O. Ojelabi, Xin D Gao, Tom S Rodriguez, Hao-Feng Cheng, Karen Kelly, Jonathan K. Watts, Jun Xie, ...
Base editors (BEs) have opened new avenues for the treatment of genetic diseases. However, advances in delivery approaches are needed to enable disease targeting of a broad range of tissues and cell types. Adeno-associated virus (AAV) vectors remain…
Base editors (BEs) have opened new avenues for the treatment of genetic diseases. However, advances in delivery approaches are needed to enable disease targeting of a broad range of tissues and cell types. Adeno-associated virus (AAV) vectors remain one of the most promising delivery vehicles for gene therapies. Currently, most BE/guide combinations and their promoters exceed the packaging limit (∼5 kb) of AAVs. Dual-AAV delivery strategies often require high viral doses that impose safety concerns. In this study, we engineered an adenine base editor (ABE) using a compact Cas9 from Neisseria meningitidis (Nme2Cas9). Compared with the well-characterized Streptococcus pyogenes Cas9-containing ABEs, ABEs using Nme2Cas9 (Nme2-ABE) possess a distinct protospacer adjacent motif (N4CC) and editing window, exhibit fewer off-target effects, and can efficiently install therapeutically relevant mutations in both human and mouse genomes. Importantly, we show that in vivo delivery of Nme2-ABE and its guide RNA by a single AAV vector can efficiently edit mouse genomic loci and revert the disease mutation and phenotype in an adult mouse model of tyrosinemia. We anticipate that Nme2-ABE, by virtue of its compact size and broad targeting range, will enable a range of therapeutic applications with improved safety and efficacy due in part to packaging in a single-vector system.
Published in
GEN Biotechnology
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3
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4 | 2022 |
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