DNA and RNA base editors can correct the majority of pathogenic single nucleotide variants

Ariel Dadush, Rona Merdler-Rabinowicz, David Gorelik, Ariel Feiglin, Ilana Buchumenski, Lipika R. Pal, Shay Ben-Aroya, Eytan Ruppin, Erez Y. Levanon

Research output: Contribution to journalArticlepeer-review

Abstract

The majority of human genetic diseases are caused by single nucleotide variants (SNVs) in the genome sequence. Excitingly, new genomic techniques known as base editing have opened efficient pathways to correct erroneous nucleotides. Due to reliance on deaminases, which have the capability to convert A to I(G) and C to U, the direct applicability of base editing might seem constrained in terms of the range of mutations that can be reverted. In this evaluation, we assess the potential of DNA and RNA base editing methods for treating human genetic diseases. Our findings indicate that 62% of pathogenic SNVs found within genes can be amended by base editing; 30% are G>A and T>C SNVs that can be corrected by DNA base editing, and most of them by RNA base editing as well, and 29% are C>T and A>G SNVs that can be corrected by DNA base editing directed to the complementary strand. For each, we also present several factors that affect applicability such as bystander and off-target occurrences. For cases where editing the mismatched nucleotide is not feasible, we introduce an approach that calculates the optimal substitution of the deleterious amino acid with a new amino acid, further expanding the scope of applicability. As personalized therapy is rapidly advancing, our demonstration that most SNVs can be treated by base editing is of high importance. The data provided will serve as a comprehensive resource for those seeking to design therapeutic base editors and study their potential in curing genetic diseases.

Original languageEnglish
Article number16
Journalnpj Genomic Medicine
Volume9
Issue number1
DOIs
StatePublished - 26 Feb 2024

Bibliographical note

Publisher Copyright:
© The Author(s) 2024.

Funding

The Genotype-Tissue Expression (GTEx) project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 31-Jan-2023. We used this database to extract all the genes that are highly expressed (above 10 transcripts per million) in the liver but lowly expressed in all other tissues (average expression below 10 transcripts per million). The same was done for the brain. The list of genes and expression levels is available in the supplementary section. The authors wish to thank Prof. Eyal Hendel for his useful suggestions. This research was supported by the Israel Science Foundation (grant numbers 2039/20 and 2637/23 to E.Y.L.), Foundation Fighting Blindness (award to S.B.-A. and E.Y.L.) and in part by the Intramural Research Program of the NIH, NCI.

FundersFunder number
National Institutes of Health
National Institute of Mental Health
National Institute on Drug Abuse
National Heart, Lung, and Blood Institute
National Human Genome Research Institute
National Cancer Institute
National Institute of Neurological Disorders and Stroke
Foundation Fighting Blindness
Israel Science Foundation2039/20, 2637/23

    Fingerprint

    Dive into the research topics of 'DNA and RNA base editors can correct the majority of pathogenic single nucleotide variants'. Together they form a unique fingerprint.

    Cite this