USH2A基因外显子13相关遗传性视网膜变性基因治疗进展

Advances on gene therapy for USH2A exon 13 related inherited retinal dystrophy

USH2A基因双等位基因致病变异可导致Usher综合征Ⅱ型和非综合征性视网膜色素变性,患者因光感受器细胞进行性丧失最终失明。USH2A基因很大,其cDNA有15,606 bp,无法使用腺相关病毒载体递送进行基因替代治疗。研究发现位于外显子13的致病变异在USH2A基因所有外显子的致病变异中占比最高,成为治疗的靶点。反义寡核苷酸、基因组编辑和RNA编辑方法对USH2A基因外显子13的干预研究,显示了潜在的治疗效果和应用前景。本文总结了USH2A基因外显子13相关的分子遗传机制、研究结果以及面临的挑战。

Biallelic pathogenic variants in the USH2A gene result in Usher syndrome typeⅡand non-syndromic retinitis pigmentosa,both of which entail the progressive loss of photoreceptors leading to blindness.The cDNA of the USH2A gene is extensive,consisting of 15606 base pairs,rendering it impractical for delivery via adeno-associated virus vectors for gene replacement therapy.Notably,exon 13 has emerged as a focal point for therapeutic intervention,given its predilection for harboring the most pathogenic variants within USH2A.Recent intervention studies targeting USH2A exon 13 through the utilization of antisense oligonucleotides,genome editing,and RNA editing approaches have exhibited promising therapeutic potential.This paper provides a comprehensive overview of the molecular mechanisms,outcome data,and the challenges associated with the application of these interventions in this domain.