Stargardt病基因治疗研究现状与进展

摘要

Stargardt病(STGD)是一种原发于视网膜色素上皮的遗传性眼病.目前普遍认同的有3个基因突变与其发病有关,分别是三磷酸腺苷结合转运子(Abca4)、超长链脂肪酸延伸酶4(Elovl4)及细胞表面标志物Prominin-1 (Prom1).通过人为基因敲除的方法已经获得了Abca4-/-、Elovl4-/-及Prom1-/-3种小鼠作为研究STGD的动物模型.基因治疗所用的转基因载体有慢病毒、腺相关病毒(AAV)和纳米颗粒等,小鼠动物模型经治疗后视网膜功能恢复明显.在动物实验的基础上,目前STGD基因治疗已经进入Ⅰ/Ⅱa期临床试验,所用的马传染性贫血慢病毒载体对人体的安全性和疗效的研究正在进行中.同时,重组AAV2/5、双链或杂交AAV等更加安全的新型大容量AAV载体的研究也已取得了一些进展.STGD基因治疗展现出继Leber先天性黑矇基因治疗取得成功之后遗传性视网膜疾病基因治疗领域又一缕令人期许的曙光.%Stargardt disease (STGD) is an inherited disorder of retinal pigment epithelium.Three genes have been found to be implicated in STGD including Abca4 (adenosine triphosphate-binding cassette,sub-family A,member 4),Elovl4 (elongation of very long chain fatty acids protein 4) and Prom1 (prominin-1).Target genes can be delivered to the retina by various methods such as lentivirus (LV) vectors,adeno-associated virus (AAV) vectors and non-viral nano-particles.The Abca4-/-,Elovl4-/-and Prom1-/ mice model are used to study the pathogenesis mechanism and treatment of STGD.Retinal function improved significantly upon gene therapy in these models.Based on these works using animal model,phase Ⅰ /Ⅱ a clinical trial of Abca4-associated STGD gene therapy are underway.As a LV vector,equine infectious anemia virus (EIAV) is used to carry the Abca4 gene.These studies will evaluate three dose levels of the EIAV vector for safety,tolerability and biological activity.Moreover,some preclinical attempts to deliver Abca4 via AAV have been made using a modified AAV vectors because of the large size of the ABCA4 cDNA.The good responses in animal models render STGD a very attractive object for human gene therapy after the successful of the phase Ⅰ /Ⅱ clinical trials of Leber's congenital amaurosis.