The Great Therapeutic Potential of Base-Editors: Mapping All Pathogenic Mutations
2Cancer Data Science Lab, Center for Cnacer Research, National Cancer Institute, National Institutes of Health, USA
3Raymond and Beverly Sackler School of Physics and Astronomy, Tel Aviv University, Israel
4Equal contribution, .
The majority of human genetic diseases are caused by a single nucleotide variant (SNV) in the genome sequence. Up until recently, genetic diseases were considered predestination; science is now advancing towards base editing (BE), an arsenal of techniques that holds the potential to modify a specific nucleotide in the genome with high efficiency. Two main family of enzymes are widely used in BE; ADAR enzymes that induce deamination of Adenosine (A) to Inosine (I) that is read as Guanosine (G), and APOBEC enzymes, which induce deamination of Cytosine (C) to Thymine (T).
In the current work we review all the known mutations in the human genome that were reported in ClinVar to cause significant pathologic diseases, and create ordered lists of the mutations that are suitable for ADAR/APOBEC based BE technologies. We also provide supplementary information for each editing option, including off-target sites and motif suitability. When a direct editing of the mutant mutation is not possible, we calculate the possibility to use ADAR/APOBEC based BE to substitute the mutant amino-acid with a less pathogenic one.
Hopefully this work will help scientists and clinicians in the process of designing successful targets for therapies, marching medicine to a future in which curing genetic diseases is feasible.