Programmable RNA editing with endogenous ADAR enzymes - a feasible option for the treatment of inherited retinal disease?
Programmable RNA editing with endogenous ADAR enzymes - a feasible option for the treatment of inherited retinal disease?
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DOI：
10.3389/fnmol.2023.1092913
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发表时间：
2023
影响因子：
4.8
通讯作者：
MacLaren, Robert E. E.
中科院分区：
文献类型：
--
作者：
Bellingrath, Julia-Sophia;McClements, Michelle E. E.;Fischer, M. Dominik;MacLaren, Robert E. E.
关键词：
RNA编辑对于人类转录组中致病性单核苷酸变异（SNV）的治疗性校正具有很大的希望，因为它不会在基因组中产生永久性脱靶编辑的风险，并且具有创新递送选项的潜力。作用于RNA的腺嘌呤脱氨酶（阿达尔）酶催化人类中最广泛形式的转录后RNA编辑，并且它们将双链RNA（dsRNA）中的腺苷水解脱氨为肌苷的能力已被利用来在转录水平上改变人类基因组中的致病性单核苷酸变体（SNV）。到目前为止，最有前途的目标编辑率已经实现了外源性递送的催化活性的阿达尔脱氨酶结构域（ADARDD）融合到RNA结合蛋白。虽然已经显示内源性ADAR可以在ADAR募集向导RNA的唯一帮助下募集到限定的靶位点，从而释放包装空间，降低针对外源蛋白的免疫应答的机会，并降低转录组范围的脱靶效应，但这种方法受到低编辑效率的限制。通过最近开发的新型环状ADAR募集向导RNA以及ADAR募集反义寡核苷酸的优化，使用内源性阿达尔的RNA编辑现在在体外和体内显示出有希望的靶编辑效率。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，在施用后立即和施用后长达6周，显示了与外源性阿达尔的RNA编辑相当的靶编辑效率。有了这些令人鼓舞的结果，用内源性阿达尔进行RNA编辑有可能为治疗遗传性视网膜疾病（IRD）提供一种有吸引力的选择，在该领域，基因替代疗法已被确立为安全有效，但对于超过腺相关病毒（AAV）的包装能力或以一种以上视网膜同种型表达的基因仍存在未满足的需求。本文综述了内源性阿达尔在RNA编辑领域的最新进展，并评估其在IRD治疗领域的适用性。
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 (ADARDD) 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.
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影响因子：
82.9
作者：
Cideciyan AV;Jacobson SG;Ho AC;Garafalo AV;Roman AJ;Sumaroka A;Krishnan AK;Swider M;Schwartz MR;Girach A
通讯作者：
Girach A
影响因子：
4.8
作者：
Cai, Xue;Conley, Shannon M.;Naash, Muna I.
通讯作者：
Naash, Muna I.
DOI：
10.1073/pnas.240464097
发表时间：
2000-12-05
影响因子：
11.1
作者：
Brown, BA;Lowenhaupt, K;Rich, A
通讯作者：
Rich, A
影响因子：
16.8
作者：
Bhalla, T;Rosenthal, JJC;Reenan, R
通讯作者：
Reenan, R
影响因子：
64.8
作者：
Burns, CM;Chu, H;Emeson, RB
通讯作者：
Emeson, RB