Lani-Louzada Rafael, Dias Mariana Santana, Linden Rafael, Ribas Vinicius Toledo, Petrs-Silva Hilda
Laboratory of Neurogenesis, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro,Brazil.
Laboratory of Neurobiology, Department of Morphology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte,Brazil.
Curr Gene Ther. 2021;21(5):362-381. doi: 10.2174/1566523221666210126152000.
Glaucoma leads to irreversible vision loss and current therapeutic strategies are often insufficient to prevent the progression of the disease and consequent blindness. Elevated intraocular pressure is an important risk factor, but not required for the progression of glaucomatous neurodegeneration. The demise of retinal ganglion cells represents the final common pathway of glaucomatous vision loss. Still, lifelong control of intraocular pressure is the only current treatment to prevent severe vision loss, although it frequently fails despite best practices. This scenario calls for the development of neuroprotective and pro-regenerative therapies targeting the retinal ganglion cells as well as the optic nerve. Several experimental studies have shown the potential of gene modulation as a tool for neuroprotection and regeneration. In this context, gene therapy represents an attractive approach as a persistent treatment for glaucoma. Viral vectors engineered to promote overexpression of a broad range of cellular factors have been shown to protect retinal ganglion cells and/or promote axonal regeneration in experimental models. Here, we review the mechanisms involved in glaucomatous neurodegeneration and regeneration in the central nervous system. Then, we point out the current limitations of gene therapy platforms and review a myriad of studies that use viral vectors to manipulate genes in retinal ganglion cells, as a strategy to promote neuroprotection and regeneration. Finally, we address the potential of combining neuroprotective and regenerative gene therapies as an approach to glaucomatous neurodegeneration.
青光眼会导致不可逆的视力丧失，而目前的治疗策略往往不足以阻止疾病的进展及随之而来的失明。眼压升高是一个重要的风险因素，但并非青光眼性神经退行性变进展所必需。视网膜神经节细胞的死亡是青光眼性视力丧失的最终共同途径。尽管如此，终身控制眼压是目前预防严重视力丧失的唯一治疗方法，尽管遵循最佳实践，其仍常常失败。这种情况需要开发针对视网膜神经节细胞以及视神经的神经保护和促再生疗法。多项实验研究表明基因调控作为神经保护和再生工具的潜力。在这种背景下，基因治疗作为一种针对青光眼的持久治疗方法具有吸引力。经工程改造以促进多种细胞因子过表达的病毒载体已被证明在实验模型中可保护视网膜神经节细胞和/或促进轴突再生。在此，我们综述中枢神经系统中青光眼性神经退行性变和再生所涉及的机制。然后，我们指出基因治疗平台目前的局限性，并综述众多使用病毒载体在视网膜神经节细胞中操纵基因的研究，作为促进神经保护和再生的策略。最后，我们探讨联合神经保护和再生基因治疗作为青光眼性神经退行性变治疗方法的潜力。
