Abstract
RNA editing aims to treat genetic disease through altering gene expression at the transcript level. Pairing site-directed RNA-targeting mechanisms with engineered deaminase enzymes allows for the programmable correction of G>A and T>C mutations in RNA. This offers a promising therapeutic approach for a range of genetic diseases. For inherited retinal degenerations caused by point mutations in large genes not amenable to single-adeno-associated viral (AAV) gene therapy such as USH2A and ABCA4, correcting RNA offers an alternative to gene replacement. Genome editing of RNA rather than DNA may offer an improved safety profile, due to the transient and potentially reversible nature of edits made to RNA. This review considers the current site-directing RNA editing systems, and the potential to translate these to the clinic for the treatment of inherited retinal degeneration.
Highlights
Programmable editing of nucleic acids offers significant therapeutic potential for a wide range of genetic diseases
Gene replacement therapy to introduce the normal copy of a gene to cells lacking gene expression in X-linked and autosomal recessive conditions has shown excellent outcomes, with an FDA-approved therapy to replace the RPE65 gene for Leber’s congenital amaurosis [4] and many others being evaluated in clinical trials [3]
A double-stranded RNA-binding domain makes direct contact with double stranded RNA, while a C-terminal deaminase domain (ADARDD) catalyses hydrolytic deamination where an amino group is replaced by a hydroxyl group, converting adenosine to inosine (Figure 2)
Summary
Programmable editing of nucleic acids offers significant therapeutic potential for a wide range of genetic diseases. Strategies that require the introduction of a correct donor template, such as homology-directed repair of double-stranded breaks have low in vivo efficiency [20,21,22] Approaches such as DNA base editing [23] or prime editing [24] can relatively efficiently introduce specific corrections without double-stranded breaks but use large constructs that are not currently deliverable with AAV vectors. We review the potential for using RNA editing enzymes for site-directed RNA editing, and how this might be applied to correct mutations in large genes implicated in inherited retinal degenerations not amenable to AAV gene therapy
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