ArticleNature biomedical engineering2026
Improved specificity and efficiency of in vivo adenine base editing therapies with hybrid guide RNAs.
Article in Nature biomedical engineering, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed.
- Advances in Precision Editing Therapies for Alpha-1 Antitrypsin Deficiency.Human gene therapy · 2026Review
- Editing around the target: epitope engineering to protect stem cell grafts.Blood advances · 2026Review
- Engineered Transformer Base Editor with Enhanced Editing Efficiency.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Pharmacological readthrough and base editing forMolecular therapy. Nucleic acids · 2026Article
- Improved specificity and efficiency of in vivo adenine base editing therapies with hybrid guide RNAs.Nature biomedical engineering · 2026Article
- Article
- Agentic AI and the rise of in silico team science in biomedical research.Nature biotechnology · 2026Review
- Glioblastoma Stem Cells as Targets for Emerging Precision Immunotherapies and Molecular Treatments.Cells · 2026Review
- Review
- Correction of a recurrent pathogenic variant in methylmalonic acidemia using adenine base editing.bioRxiv : the preprint server for biology · 2026Article
- The New Wave of Gene and Cell Therapies Across Diseases.Journal of clinical medicine · 2026Review
- Sensitive and unbiased genome-wide profiling of base-editor-induced off-target activity using CHANGE-seq-BE.Nature biotechnology · 2026Article
- Liver-directed base editing ofMolecular therapy. Nucleic acids · 2025Article
- Benchmarking matters.Nature biomedical engineering · 2025Article
Corrections and comments
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Authors and funding
19 authors.
Funding
Abstract
Phenylketonuria (PKU), pseudoxanthoma elasticum (PXE) and hereditary tyrosinemia type 1 (HT1) are autosomal recessive disorders linked to the PAH, ABCC6, and FAH and HPD genes, respectively. Here we evaluate the off-target editing profiles of clinical lead guide RNAs (gRNAs) that, when combined with adenine base editors (ABEs), correct the recurrent PAH P281L variant, PAH R408W variant or ABCC6 R1164X variant, or disrupt either of two sites in the HPD gene (a modifier gene of HT1) in human hepatocytes. To mitigate off-target mutagenesis, we systematically screen hybrid gRNAs with DNA nucleotide substitutions. Comprehensive and variant-aware specificity profiling of these hybrid gRNAs reveals dramatically reduced off-target editing and reduced bystander editing in cells. In humanized PAH P281L and ABCC6 R1164X mouse models of PKU and PXE, we show that when formulated in lipid nanoparticles with ABE messenger RNA, selected hybrid gRNAs revert disease phenotypes, reduce off-target editing, increase on-target editing and reduce bystander editing in vivo. These studies highlight the use of hybrid gRNAs to improve the safety and efficiency of adenine base-editing therapies.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.