Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA, United States.
Handb Clin Neurol. 2024;205:243-262. doi: 10.1016/B978-0-323-90120-8.00016-2.
Leading causes of blindness worldwide include neurodegenerative diseases of the retina, which cause irreversible loss of retinal pigment epithelium (RPE) and photoreceptors, and optic neuropathies, which result in retinal ganglion cell (RGC) death. Because photoreceptor and RGCs do not spontaneously regenerate in mammals, including humans, vision loss from these conditions is, at present, permanent. Recent advances in gene and cell-based therapies have provided new hope to patients affected by these conditions. This chapter reviews the current state and future of these approaches to treating ocular neurodegenerative disease. Gene therapies for retinal degeneration and optic neuropathies primarily focus on correcting known pathogenic mutations that cause inherited conditions to halt progression. There are multiple retinal and optic neuropathy gene therapies in clinical trials, and one retinal gene therapy is approved in the United States, Canada, Europe, and Australia. Cell-based therapies are mutation agnostic and have the potential to repopulate neurons regardless of the underlying etiology of degeneration. While photoreceptor cell replacement is nearing a human clinical trial, RPE transplantation is currently in phase I/II clinical trials. RGC replacement faces numerous logistical challenges, but preclinical research has laid the foundation for functional repair of optic neuropathies to be feasible.
全球范围内导致失明的主要原因包括视网膜神经退行性疾病，这些疾病会导致视网膜色素上皮（RPE）和光感受器的不可逆转损失，以及视神经病变，从而导致视网膜神经节细胞（RGC）死亡。由于包括人类在内的哺乳动物中感光器和 RGC 不会自发再生，因此这些情况下的视力丧失目前是永久性的。最近在基因和细胞为基础的治疗方法方面的进展为受这些疾病影响的患者提供了新的希望。本章回顾了治疗眼部神经退行性疾病的这些方法的现状和未来。针对视网膜变性和视神经病变的基因治疗主要集中在纠正导致遗传性疾病的已知致病突变，以阻止其进展。目前有多种视网膜和视神经病变的基因治疗正在临床试验中，一种视网膜基因治疗已在美国、加拿大、欧洲和澳大利亚获得批准。基于细胞的治疗方法与突变无关，并且具有潜在能力，无论退化的潜在病因如何，都可以重新填充神经元。虽然光感受器细胞置换术已接近人体临床试验，但 RPE 移植目前正在进行 I/II 期临床试验。RGC 置换术面临许多实际操作方面的挑战，但临床前研究为视神经病变的功能修复奠定了基础，使其成为可行的方法。
