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X连锁视网膜色素变性基因治疗的临床前和临床进展:曙光在望。

Pre-Clinical and Clinical Advances in Gene Therapy of X-Linked Retinitis Pigmentosa: Hope on the Horizon.

作者信息

Pechnikova Nadezhda A, Poimenidou Malamati, Iliadis Ioannis, Zafeiriou-Chatziefraimidou Maria, Iaremenko Aleksandra V, Yaremenko Tamara V, Domvri Kalliopi, Yaremenko Alexey V

机构信息

Department of Biochemistry and Biotechnology, University of Thessaly, 38446 Volos, Greece.

Laboratory of Chemical Engineering A', Department of Chemical Engineering, Faculty of Engineering, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece.

出版信息

J Clin Med. 2025 Jan 29;14(3):898. doi: 10.3390/jcm14030898.

Abstract

X-linked retinitis pigmentosa (XLRP) is a severe inherited retinal degenerative disease characterized by progressive loss of photoreceptors and retinal pigment epithelium, leading to blindness. Predominantly affecting males due to mutations in the RPGR gene, XLRP currently lacks effective treatments beyond supportive care. Gene therapy has emerged as a promising approach to restore photoreceptor function by delivering functional copies of the RPGR gene. Recent clinical trials using AAV vectors, such as AAV5-RPGR and AGTC-501, have demonstrated encouraging results, including improvements in retinal sensitivity and visual function. While early successes like LUXTURNA have set the precedent for gene therapy in retinal diseases, adapting these strategies to XLRP presents unique challenges due to the complexity of RPGR mutations and the need for efficient photoreceptor targeting. Advances in vector design, including the use of optimized AAV serotypes with enhanced tropism for photoreceptors and specific promoters, have significantly improved gene delivery. Despite setbacks in some studies, ongoing research and clinical trials continue to refine these therapies, offering hope for patients affected by XLRP. This review explores the etiology and pathophysiology of XLRP, evaluates current treatment challenges, highlights recent clinical advances in gene therapy, and discusses future perspectives for bringing these therapies into clinical practice.

摘要

X连锁视网膜色素变性(XLRP)是一种严重的遗传性视网膜退行性疾病,其特征是光感受器和视网膜色素上皮进行性丧失,最终导致失明。由于RPGR基因突变,该病主要影响男性,目前除了支持性治疗外,缺乏有效的治疗方法。基因治疗已成为一种有前景的方法,通过递送RPGR基因的功能拷贝来恢复光感受器功能。最近使用腺相关病毒(AAV)载体(如AAV5-RPGR和AGTC-501)的临床试验取得了令人鼓舞的结果,包括视网膜敏感性和视觉功能的改善。虽然像LUXTURNA这样的早期成功为视网膜疾病的基因治疗树立了先例,但由于RPGR突变的复杂性以及高效靶向光感受器的需求,将这些策略应用于XLRP面临着独特的挑战。载体设计的进展,包括使用对光感受器具有增强嗜性的优化AAV血清型和特定启动子,显著改善了基因递送。尽管在一些研究中遇到挫折,但正在进行的研究和临床试验继续完善这些疗法,为受XLRP影响的患者带来了希望。这篇综述探讨了XLRP的病因和病理生理学,评估了当前的治疗挑战,突出了基因治疗的最新临床进展,并讨论了将这些疗法应用于临床实践的未来前景。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5203/11818521/335d05aec522/jcm-14-00898-g002.jpg

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