Pniakowska Zofia, Dzieża Natasza, Kustosik Natalia, Przybylak Aleksandra, Jurowski Piotr
Department of Ophthalmology and Vision Rehabilitation, Medical University of Lodz, 90-549 Lodz, Poland.
Optegra Eye Clinic, 90-127 Lodz, Poland.
J Clin Med. 2025 Aug 11;14(16):5661. doi: 10.3390/jcm14165661.
Retinitis pigmentosa is a group of inherited retinal dystrophies characterized by progressive photoreceptor cell loss leading to irreversible vision loss. Affecting approximately 1 in 4000 individuals worldwide, retinitis pigmentosa exhibits significant genetic heterogeneity, with mutations in genes such as , , , , and , which contribute to its diverse clinical presentation. This review outlines the genetic basis of retinitis pigmentosa and explores cutting-edge gene-based therapeutic strategies. Luxturna (voretigene neparvovec-rzyl), the first FDA-approved gene therapy targeting mutations, represents a milestone in precision ophthalmology, while OCU400 is a gene-independent therapy that uses a modified construct to modulate retinal homeostasis across different RP genotypes. Additionally, CRISPR-Cas genome-editing technologies offer future potential for the personalized correction of specific mutations, though concerns about off-target effects and delivery challenges remain. The article also highlights MCO-010, a novel optogenetic therapy that bypasses defective phototransduction pathways, showing promise for patients regardless of their genetic profile. Moreover, QR-1123, a mutation-specific antisense oligonucleotide targeting the P23H variant in the gene, is under clinical investigation for autosomal dominant RP and has shown encouraging preclinical results in reducing toxic protein accumulation and preserving photoreceptors. SPVN06, another promising candidate, is a mutation-agnostic gene therapy delivering RdCVF and RdCVFL via AAV to support cone viability and delay degeneration, currently being evaluated in a multicenter Phase I/II trial for patients with various rod-cone dystrophies. Collectively, these advances illustrate the transition from symptom management toward targeted, mutation-specific therapies, marking a major advancement in the treatment of RP and inherited retinal diseases.
视网膜色素变性是一组遗传性视网膜营养不良，其特征是光感受器细胞进行性丧失，导致不可逆的视力丧失。视网膜色素变性在全球约每4000人中就有1人受影响，表现出显著的遗传异质性， 、 、 、 和 等基因的突变导致了其多样的临床表现。本综述概述了视网膜色素变性的遗传基础，并探讨了前沿的基于基因的治疗策略。Luxturna（voretigene neparvovec-rzyl）是首个获得美国食品药品监督管理局批准的针对 突变的基因疗法，代表了精准眼科的一个里程碑，而OCU400是一种不依赖基因的疗法，它使用一种修饰的 构建体来调节不同视网膜色素变性基因型的视网膜内环境稳定。此外，CRISPR-Cas基因组编辑技术为特定突变的个性化纠正提供了未来潜力，尽管对脱靶效应和递送挑战的担忧仍然存在。文章还重点介绍了MCO-010，这是一种新型光遗传学疗法，可绕过有缺陷的光转导途径，对无论其基因特征如何的患者都显示出前景。此外，QR-1123是一种针对 基因中P23H变体的突变特异性反义寡核苷酸，正在针对常染色体显性视网膜色素变性进行临床研究，并且在减少毒性蛋白积累和保护光感受器方面已显示出令人鼓舞的临床前结果。另一个有前景的候选药物SPVN06是一种不依赖突变的基因疗法，通过腺相关病毒递送RdCVF和RdCVFL以支持视锥细胞活力并延缓退化，目前正在针对患有各种视杆-视锥营养不良的患者进行多中心I/II期试验评估。总体而言，这些进展说明了从症状管理向靶向、突变特异性疗法的转变，标志着视网膜色素变性和遗传性视网膜疾病治疗的重大进步。
