Bellingrath Julia-Sophia, McClements Michelle E, Fischer M Dominik, MacLaren Robert E
Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.
Oxford Eye Hospital, Oxford University Hospitals NHS Trust, Oxford, United Kingdom.
Front Mol Neurosci. 2023 May 24;16:1092913. doi: 10.3389/fnmol.2023.1092913. eCollection 2023.
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) 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 and . 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.
RNA编辑在治疗人类转录组中的致病性单核苷酸变异（SNV）方面具有巨大潜力，因为它不会在基因组中产生永久性脱靶编辑风险，并且具有创新的递送选择潜力。作用于RNA的腺嘌呤脱氨酶（ADAR）催化人类转录后RNA编辑中最广泛的形式，它们在双链RNA（dsRNA）中将腺苷水解脱氨为肌苷的能力已被用于在转录水平上改变人类基因组中的致病性单核苷酸变异（SNV）。到目前为止，最有前景的靶向编辑率是通过外源性递送与RNA结合蛋白融合的催化活性ADAR脱氨酶结构域（ADAR）实现的。虽然已经表明，仅借助ADAR招募引导RNA就可以将内源性ADAR招募到特定靶位点，从而释放包装空间，降低对外源蛋白产生免疫反应的机会，并减少全转录组范围的脱靶效应，但这种方法一直受到编辑效率低的限制。通过最近新型环状ADAR招募引导RNA的开发以及ADAR招募反义寡核苷酸的优化，利用内源性ADAR进行的RNA编辑现在显示出有前景的靶向编辑效率。在野生型和疾病小鼠模型以及野生型非人灵长类动物（NHP）中，应用后立即以及应用后长达6周，都显示出与外源性ADAR进行RNA编辑相当的靶向编辑效率。有了这些令人鼓舞的结果，利用内源性ADAR进行RNA编辑有可能为遗传性视网膜疾病（IRD）的治疗提供一个有吸引力的选择，在这个领域，基因替代疗法已被确立为安全有效的，但对于超过腺相关病毒（AAV）包装能力或在多种视网膜异构体中表达的基因，仍存在未满足的需求。本综述旨在概述利用内源性ADAR进行RNA编辑领域的最新进展，并评估其在IRD治疗领域的适用性。
