Novel Engineered Programmable Systems for ADAR-Mediated RNA Editing

One of the most prevalent forms of post-transcriptional RNA modification is the conversion of adenosine-to-inosine (A-to-I), mediated by adenosine deaminase acting on RNA (ADAR) enzymes. The advent of the CRISPR/Cas systems inspires researchers to work actively in the engineering of programmable RNA-guided machines for basic research and biomedical applications. In this regard, CIRTS (CRISPR-Cas-Inspired RNA Targeting System), RESCUE (RNA Editing for Specific C to U Exchange), RESTORE (Recruiting Endogenous ADAR to Specific Transcripts for Oligonucleotide-mediated RNA Editing), and LEAPER (Leveraging Endogenous ADAR for Programmable Editing of RNA) are innovative RNA base-editing platforms that have recently been engineered to perform programmable base conversions on target RNAs mediated by ADAR enzymes in mammalian cells. Thus, these four currently characterized RNA-editing systems constitute novel molecular tools with compelling programmability, specificity, and efficiency that show us some creative ways to take advantage of the engineered deaminases for precise base editing. Moreover, the advanced engineering of these systems permits editing of full-length transcripts containing disease-causing point mutations without the loss of genomic information, providing an attractive alternative for in vivo research and in the therapeutic setting if the challenges encountered in off-target edits and delivery are appropriately addressed. Here, I present an analytical approach of the current status and rapid progress of the novel ADAR-mediated RNA-editing systems when highlighting the qualities of each new RNA-editing platform and how these RNA-targeting strategies could be used to recruit human ADARs on endogenous transcripts, not only for our understanding of RNA-modification-mediated regulation of gene expression but also for editing clinically relevant mutations in a programmable and straightforward manner.