Harvey Joshua Paul, Sladen Paul Edward, Yu-Wai-Man Patrick, Cheetham Michael E
UCL Institute of Ophthalmology (JPH, PES, PY-W-M, MC), London, United Kingdom; Moorfields Eye Hospital NHS Foundation Trust (JPH, PY-W-M), London, United Kingdom; Department of Clinical Neurosciences (PY-W-M), Cambridge Centre for Brain Repair, University of Cambridge, Cambridge, United Kingdom; and Department of Clinical Neurosciences (PY-W-M), John van Geest Centre for Brain Repair and MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, United Kingdom.
J Neuroophthalmol. 2022 Mar 1;42(1):35-44. doi: 10.1097/WNO.0000000000001375. Epub 2021 Sep 30.
Inherited optic neuropathies (IONs) cause progressive irreversible visual loss in children and young adults. There are limited disease-modifying treatments, and most patients progress to become severely visually impaired, fulfilling the legal criteria for blind registration. The seminal discovery of the technique for reprogramming somatic nondividing cells into induced pluripotent stem cells (iPSCs) has opened several exciting opportunities in the field of ION research and treatment.
A systematic review of the literature was conducted with PubMed using the following search terms: autosomal dominant optic atrophy, ADOA, dominant optic atrophy, DOA, Leber hereditary optic neuropathy, LHON, optic atrophy, induced pluripotent stem cell, iPSC, iPSC derived, iPS, stem cell, retinal ganglion cell, and RGC. Clinical trials were identified on the ClinicalTrials.gov website.
This review article is focused on disease modeling and the therapeutic strategies being explored with iPSC technologies for the 2 most common IONs, namely, dominant optic atrophy and Leber hereditary optic neuropathy. The rationale and translational advances for cell-based and gene-based therapies are explored, as well as opportunities for neuroprotection and drug screening.
iPSCs offer an elegant, patient-focused solution to the investigation of the genetic defects and disease mechanisms underpinning IONs. Furthermore, this group of disorders is uniquely amenable to both the disease modeling capability and the therapeutic potential that iPSCs offer. This fast-moving area will remain at the forefront of both basic and translational ION research in the coming years, with the potential to accelerate the development of effective therapies for patients affected with these blinding diseases.
遗传性视神经病变（IONs）可导致儿童和年轻人出现进行性不可逆视力丧失。疾病改善治疗方法有限，大多数患者会进展为严重视力障碍，符合盲人登记的法定标准。将体细胞重编程为诱导多能干细胞（iPSCs）技术的开创性发现为ION研究和治疗领域带来了几个令人兴奋的机遇。
使用以下检索词在PubMed上对文献进行了系统综述：常染色体显性视神经萎缩、ADOA、显性视神经萎缩、DOA、Leber遗传性视神经病变、LHON、视神经萎缩、诱导多能干细胞、iPSC、iPSC衍生的、iPS、干细胞、视网膜神经节细胞和RGC。在ClinicalTrials.gov网站上识别了临床试验。
这篇综述文章重点关注了针对两种最常见的IONs，即显性视神经萎缩和Leber遗传性视神经病变，利用iPSC技术进行疾病建模和探索治疗策略。探讨了基于细胞和基于基因疗法的基本原理和转化进展，以及神经保护和药物筛选的机会。
iPSCs为研究IONs的遗传缺陷和疾病机制提供了一种优雅的、以患者为中心的解决方案。此外，这组疾病特别适合iPSCs所具备的疾病建模能力和治疗潜力。在未来几年，这个快速发展的领域将继续处于ION基础研究和转化研究的前沿，有可能加速为受这些致盲疾病影响的患者开发有效疗法。
