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Updated: Feb 7, 2026

Enhanced Gene Delivery and Expression using Intraosseous Injection of Chitosan Nanoparticles Encapsulated Adenine Base Editor Plasmids
Published on: May 16, 2025
Therapeutic adenine base editor with minimized off-target effects
Yongsen Sun1, Nana Yan1, Hu Feng1
1State Key Laboratory of Genome and Multi-omics Technologies, Shenzhen Branch, Guangdong Laboratory of Lingnan Modern Agriculture, Key Laboratory of Gene Editing Technologies (Hainan), Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen 518120, China.
Abstract:
Genome-wide off-target effect poses a safety risk for clinical use of adenine base editor (ABE), among which ABE8e is one of the most efficient. Genome-wide off-target analysis by two-cell embryo injection (GOTI) analysis showed that the rate of genome-wide single-nucleotide variants (SNVs) in ABE8e-edited cells was ∼30-fold higher than that of spontaneous SNVs in control cells, indicating prevalent off-target effects of ABE8e, but no off-target effect for ABE7.10, from which ABE8e was derived. We performed saturation mutagenesis of eight amino acid sites of the deaminase (TadA8e) within ABE8e and obtained ABE8eY149V that exhibited high editing efficiency without detectable off-target effect. Furthermore, TadA8eY149V could be fused with other Cas homologs (PAM-relaxed SpRY, hypercompact SaKKH, or IscB) to expand its target range. Finally, ABE8eY149V editing of hydroxyphenylpyruvate dioxygenase (Hpd) gene prevented lethality in hereditary tyrosinemia type I mice. The high efficiency and fidelity of ABE8eY149V suggest its potential application in ABE-based gene therapies.
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