School of Anatomy and Human Biology, The University of Western Australia, Nedlands, WA, Australia.
Curr Gene Ther. 2011 Apr;11(2):116-31. doi: 10.2174/156652311794940746.
Recent clinical trials have shown that the use of replication deficient viral vectors to genetically modify cells in the retina can be of therapeutic benefit in the treatment of certain inherited degenerative conditions that compromise photoreceptor, and hence visual, function. This review is focussed primarily on the use of recombinant adeno-associated viral (rAAV) vectors to target neurons in inner retina, specifically retinal ganglion cells (RGCs). Genetic modification of RGCs may be of value in various ophthalmic conditions in which there is documented loss of RGCs or damage to their centrally projecting axons. Such conditions include glaucoma, optic neuritis, vascular disruption or trauma, and neurological degenerative conditions such as Alzheimer's disease. Furthermore, because the retina and optic nerve (ON) form part of the CNS, the visual system is a useful experimental model in which to study the molecular and cellular mechanisms that underlie degenerative as well as regenerative responses of adult CNS neurons after injury. Gene therapy studies from a number of laboratories are first reviewed, involving not only rAAV-based treatments but also application of lentiviral and adenoviral vectors. Recent work from our own laboratory is then summarized, in which intravitreal injection of rAAV2 serotype vectors is used to introduce growth promoting genes into injured RGCs. rAAV encoding a secretable form of ciliary neurotrophic factor (CNTF) has proved to be particularly effective in promoting RGC survival and axon regeneration after optic nerve crush or after transection followed by a peripheral nerve autograft. In the latter situation we have found that RGCs and their regenerated axons are maintained for at least 15 months after the initial injury. We have also combined rAAV gene therapy with pharmacotherapy to determine if cAMP elevation and additional intravitreal injections of growth factors can act synergistically with vector-based delivery of growth-promoting genes.
最近的临床试验表明，使用复制缺陷型病毒载体对视网膜细胞进行基因修饰，在治疗某些遗传性退行性疾病方面具有治疗益处，这些疾病会损害光感受器，从而影响视力。本综述主要关注使用重组腺相关病毒（rAAV）载体来靶向内视网膜神经元，特别是视网膜神经节细胞（RGC）。RGC 的基因修饰可能对各种眼科疾病具有价值，这些疾病有 RGC 丢失或其向中枢投射轴突受损的记录。这些情况包括青光眼、视神经炎、血管中断或创伤以及神经退行性疾病，如阿尔茨海默病。此外，由于视网膜和视神经（ON）是中枢神经系统的一部分，因此视觉系统是一个有用的实验模型，可以研究成年中枢神经系统神经元在损伤后退行性和再生反应的分子和细胞机制。首先回顾了来自多个实验室的基因治疗研究，不仅涉及基于 rAAV 的治疗，还涉及慢病毒和腺病毒载体的应用。然后总结了我们自己实验室的最新工作，其中通过玻璃体内注射 rAAV2 血清型载体将生长促进基因引入受损的 RGC。编码可分泌型睫状神经营养因子（CNTF）的 rAAV 已被证明在视神经挤压或切断后再进行外周神经自体移植后促进 RGC 存活和轴突再生方面特别有效。在后一种情况下，我们发现 RGC 及其再生轴突在初始损伤后至少可维持 15 个月。我们还将 rAAV 基因治疗与药物治疗相结合，以确定 cAMP 升高和额外的玻璃体内生长因子注射是否可以与载体递送的生长促进基因协同作用。
