PMID- 37293541
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240320
IS  - 1662-5099 (Print)
IS  - 1662-5099 (Electronic)
IS  - 1662-5099 (Linking)
VI  - 16
DP  - 2023
TI  - Programmable RNA editing with endogenous ADAR enzymes - a feasible option for the 
      treatment of inherited retinal disease?
PG  - 1092913
LID - 10.3389/fnmol.2023.1092913 [doi]
LID - 1092913
AB  - RNA editing holds great promise for the therapeutic correction of pathogenic, 
      single nucleotide variants (SNV) in the human transcriptome since it does not 
      risk creating permanent off-targets edits in the genome and has the potential for 
      innovative delivery options. Adenine deaminases acting on RNA (ADAR) enzymes 
      catalyse the most widespread form of posttranscriptional RNA editing in humans 
      and their ability to hydrolytically deaminate adenosine to inosine in double 
      stranded RNA (dsRNA) has been harnessed to change pathogenic single nucleotide 
      variants (SNVs) in the human genome on a transcriptional level. Until now, the 
      most promising target editing rates have been achieved by exogenous delivery of 
      the catalytically active ADAR deaminase domain (ADAR(DD)) fused to an RNA binding 
      protein. While it has been shown that endogenous ADARs can be recruited to a 
      defined target site with the sole help of an ADAR-recruiting guide RNA, thus 
      freeing up packaging space, decreasing the chance of an immune response against a 
      foreign protein, and decreasing transcriptome-wide off-target effects, this 
      approach has been limited by a low editing efficiency. Through the recent 
      development of novel circular ADAR-recruiting guide RNAs as well as the 
      optimisation of ADAR-recruiting antisense oligonucleotides, RNA editing with 
      endogenous ADAR is now showing promising target editing efficiency in vitro and 
      in vivo. A target editing efficiency comparable to RNA editing with exogenous 
      ADAR was shown both in wild-type and disease mouse models as well as in wild-type 
      non-human primates (NHP) immediately following and up to 6 weeks after 
      application. With these encouraging results, RNA editing with endogenous ADAR has 
      the potential to present an attractive option for the treatment of inherited 
      retinal diseases (IRDs), a field where gene replacement therapy has been 
      established as safe and efficacious, but where an unmet need still exists for 
      genes that exceed the packaging capacity of an adeno associated virus (AAV) or 
      are expressed in more than one retinal isoform. This review aims to give an 
      overview of the recent developments in the field of RNA editing with endogenous 
      ADAR and assess its applicability for the field of treatment of IRD.
CI  - Copyright (c) 2023 Bellingrath, McClements, Fischer and MacLaren.
FAU - Bellingrath, Julia-Sophia
AU  - Bellingrath JS
AD  - Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical 
      Neurosciences, University of Oxford, Oxford, United Kingdom.
FAU - McClements, Michelle E
AU  - McClements ME
AD  - Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical 
      Neurosciences, University of Oxford, Oxford, United Kingdom.
FAU - Fischer, M Dominik
AU  - Fischer MD
AD  - Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical 
      Neurosciences, University of Oxford, Oxford, United Kingdom.
AD  - Oxford Eye Hospital, Oxford University Hospitals NHS Trust, Oxford, United 
      Kingdom.
FAU - MacLaren, Robert E
AU  - MacLaren RE
AD  - Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical 
      Neurosciences, University of Oxford, Oxford, United Kingdom.
AD  - Oxford Eye Hospital, Oxford University Hospitals NHS Trust, Oxford, United 
      Kingdom.
LA  - eng
GR  - MC_PC_19049/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Review
DEP - 20230524
PL  - Switzerland
TA  - Front Mol Neurosci
JT  - Frontiers in molecular neuroscience
JID - 101477914
PMC - PMC10244592
OTO - NOTNLM
OT  - RNA editing
OT  - adenine deaminase acting on RNA (ADAR)
OT  - adeno-associated virus (AAV) vectors
OT  - circular guide RNA
OT  - inherited retinal degeneration (IRD)
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2023/06/09 06:42
MHDA- 2023/06/09 06:43
PMCR- 2023/01/01
CRDT- 2023/06/09 04:37
PHST- 2022/11/08 00:00 [received]
PHST- 2023/04/27 00:00 [accepted]
PHST- 2023/06/09 06:43 [medline]
PHST- 2023/06/09 06:42 [pubmed]
PHST- 2023/06/09 04:37 [entrez]
PHST- 2023/01/01 00:00 [pmc-release]
AID - 10.3389/fnmol.2023.1092913 [doi]
PST - epublish
SO  - Front Mol Neurosci. 2023 May 24;16:1092913. doi: 10.3389/fnmol.2023.1092913. 
      eCollection 2023.