视网膜疾病基因治疗的现状与未来

Current situation and the future of retinal gene therapy

近年来人类基因组学研究的不断深入，基因突变检测的方法日新月异，尤其是基因芯片和全外显子扫描技术的出现，使突变基因检测变得更加简单和高效，越来越多的导致视网膜疾病的突变基因被确认。一些自然动物模型和基因敲除动物模型广泛应用于实验研究，促进了视网膜变性类疾病治疗研究的进展。此外，由于基因转染载体技术的进步，视网膜变性疾病的基因治疗研究也取得了长足的进步。随着2008年开始的Leber先天性黑嚎（LCA2）临床试验的顺利开展，为更多的隐性遗传性视网膜变性类疾病的基因治疗奠定了良好的基础，如应用基因替代疗法治疗MERTK基因突变引起的视网膜色素变性（RP）、ABCA4基因突变引起的青少年型黄斑变性、USH2A基因突变引起尤赛综合征、CHM基因突变引起先天性无脉络膜症以及应用血管内皮生长因子（VEGF）抗体疗法治疗年龄相关性黄班变性等均已相继进入临床试验阶段。基因治疗虽然有广阔的应用前景，但早期基因诊断和早期基因治疗是获得长期稳定疗效的基本条件，而对中晚期视网膜变性类疾病的治疗方法还需要改进和完善，基因替代治疗和抗凋亡／神经营养因子相结合的新疗法可能是一个较好的选择。

Following the development of technologies in molecular biology,more and more mutant genes that cause retinal degenerative diseases have been found. Meanwhile, many naturally occurring or genetically engineered animal models have showed similar gene mutations and phenotypes as the human inherited retinal diseases,which have led to the development of a variety of therapeutic strategies for those traditionally incurable inherited diseases. Following Leber congenital amaurosis 2 （LCA2） gene therapy clinical trial, more gene therapy clinical trials including retinitis pigmentosa （RP） with MERTK mutation, Stargardt disease with ABCA4 mutation, Usher syndrome with MYO7A mutation and age-related macular degeneration （AMD） are ongoing. Adeno associated virtal （AAV） vector- mediated gene replacement therapy that covers the whole retina showed great potential to cure early stage of those patients;while, gene replacement therapy combined with other approaches like treatment with anti-apoptotic agent and/or neurotropic factor,which can extend the therapeutic window in middle to late stages of those patients, is a potentially promising strategy for improving photoreceptor function and significantly slowing the process of retinal degeneration.