Buch Prateek K, MacLaren Robert E, Ali Robin R
Division of Molecular Therapy, UCL Institute of Ophthalmology, Bath St, London EC1V 9EL, UK.
Curr Gene Ther. 2007 Dec;7(6):434-45. doi: 10.2174/156652307782793531.
Inherited retinal degeneration (IRD) affects around 1/3000 of the population in Europe and the United States. It is a diverse group of conditions that results from mutations in any one of over 100 different genes. Many of the genes have now been identified and their functions elucidated, providing a major impetus to develop gene-based treatments. Whilst gene replacement and gene silencing strategies offer prospects for the treatment of specific inherited retinal disorders, other disorders may be less amenable to these corrective approaches. These conditions include, in particular, those associated with abnormal retinal development and those in which retinal degeneration is advanced at birth. Furthermore, the development of individualized corrective gene therapy strategies for patients with disorders due to very rare mutations may be unfeasible. However, generic gene therapy strategies that aim not to correct the gene defect but to ameliorate its consequences offer the possibility of therapies that are widely applicable across a range of conditions. One potential strategy in these cases is to halt or delay the process of cell death, so that useful visual function can be maintained throughout the lifetime of an affected individual. It has been shown in variety of experimental models over the last three decades, that neurotrophic factors have the potential to delay neuronal apoptosis. Neurotrophic factors are small proteins which have relatively short half lives and a requirement for repeated administration has limited their clinical application. Since these proteins do not ordinarily cross the blood-brain barrier, previous approaches have relied upon intrathecal infusion pumps or similar complex devices to sustain elevated neurotrophin levels within the central nervous system (CNS). However, sustained delivery through viral vector mediated expression of genes encoding neurotrophic factors may circumvent the potential side effects of repeated administration. In this review we shall explore some of the concepts of neurotrophic gene therapy and how this might be applicable to preserving vision in inherited retinal degenerations.
遗传性视网膜变性（IRD）在欧洲和美国影响着约1/3000的人口。它是一组由100多种不同基因中的任何一种发生突变引起的多种病症。现在许多基因已被鉴定出来，其功能也已阐明，这为开发基于基因的治疗方法提供了主要动力。虽然基因替代和基因沉默策略为治疗特定的遗传性视网膜疾病提供了前景，但其他疾病可能不太适合这些矫正方法。这些病症尤其包括那些与视网膜发育异常相关的病症以及那些在出生时视网膜变性就已进展的病症。此外，为因非常罕见的突变而患病的患者制定个性化的矫正基因治疗策略可能不可行。然而，旨在不纠正基因缺陷而是改善其后果的通用基因治疗策略提供了可广泛应用于一系列病症的治疗可能性。在这些情况下，一种潜在的策略是停止或延缓细胞死亡过程，以便在受影响个体的一生中维持有用的视觉功能。在过去三十年的各种实验模型中已经表明，神经营养因子有潜力延缓神经元凋亡。神经营养因子是小蛋白质，半衰期相对较短，重复给药的需求限制了它们的临床应用。由于这些蛋白质通常不会穿过血脑屏障，以前的方法依赖于鞘内输注泵或类似的复杂装置来维持中枢神经系统（CNS）内神经营养素水平的升高。然而，通过病毒载体介导的编码神经营养因子的基因表达进行持续递送可能会规避重复给药的潜在副作用。在这篇综述中，我们将探讨神经营养基因治疗的一些概念以及这如何适用于在遗传性视网膜变性中保护视力。
