Kumar Satheesh, Fry Lewis E, Wang Jiang-Hui, Martin Keith R, Hewitt Alex W, Chen Fred K, Liu Guei-Sheung
Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC, Australia; Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia.
Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK; Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
Prog Retin Eye Res. 2023 Jan;92:101110. doi: 10.1016/j.preteyeres.2022.101110. Epub 2022 Jul 13.
Genetic medicine is offering hope as new therapies are emerging for many previously untreatable diseases. The eye is at the forefront of these advances, as exemplified by the approval of Luxturna® by the United States Food and Drug Administration (US FDA) in 2017 for the treatment of one form of Leber Congenital Amaurosis (LCA), an inherited blindness. Luxturna® was also the first in vivo human gene therapy to gain US FDA approval. Numerous gene therapy clinical trials are ongoing for other eye diseases, and novel delivery systems, discovery of new drug targets and emerging technologies are currently driving the field forward. Targeting RNA, in particular, is an attractive therapeutic strategy for genetic disease that may have safety advantages over alternative approaches by avoiding permanent changes in the genome. In this regard, antisense oligonucleotides (ASO) and RNA interference (RNAi) are the currently popular strategies for developing RNA-targeted therapeutics. Enthusiasm has been further fuelled by the emergence of clustered regularly interspersed short palindromic repeats (CRISPR)-CRISPR associated (Cas) systems that allow targeted manipulation of nucleic acids. RNA-targeting CRISPR-Cas systems now provide a novel way to develop RNA-targeted therapeutics and may provide superior efficiency and specificity to existing technologies. In addition, RNA base editing technologies using CRISPR-Cas and other modalities also enable precise alteration of single nucleotides. In this review, we showcase advances made by RNA-targeting systems for ocular disease, discuss applications of ASO and RNAi technologies, highlight emerging CRISPR-Cas systems and consider the implications of RNA-targeting therapeutics in the development of future drugs to treat eye disease.
随着许多先前无法治疗的疾病出现了新的疗法，基因医学带来了希望。眼睛处于这些进展的前沿，2017年美国食品药品监督管理局（US FDA）批准Luxturna®用于治疗一种遗传性失明——莱伯先天性黑蒙（LCA）的一种形式，这就是例证。Luxturna®也是首个获得美国食品药品监督管理局批准的体内人类基因疗法。针对其他眼部疾病的众多基因疗法临床试验正在进行中，新型递送系统、新药物靶点的发现以及新兴技术目前正在推动该领域向前发展。特别是靶向RNA，对于遗传疾病来说是一种有吸引力的治疗策略，通过避免基因组的永久变化，可能比其他方法具有安全优势。在这方面，反义寡核苷酸（ASO）和RNA干扰（RNAi）是目前开发靶向RNA疗法的流行策略。成簇规律间隔短回文重复序列（CRISPR）-CRISPR相关（Cas）系统的出现进一步激发了人们的热情，该系统允许对核酸进行靶向操作。靶向RNA的CRISPR-Cas系统现在提供了一种开发靶向RNA疗法的新方法，并且可能比现有技术具有更高的效率和特异性。此外，使用CRISPR-Cas和其他方式的RNA碱基编辑技术也能够精确改变单个核苷酸。在这篇综述中，我们展示了靶向RNA系统在眼部疾病方面取得的进展，讨论了ASO和RNAi技术的应用，强调了新兴的CRISPR-Cas系统，并考虑了靶向RNA疗法在未来治疗眼部疾病药物开发中的意义。
