Berman-Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA.
Gene Ther. 2010 Jan;17(1):117-31. doi: 10.1038/gt.2009.104. Epub 2009 Aug 27.
Aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1) is required for the biosynthesis of photoreceptor phosphodiesterase (PDE). Gene defects in AIPL1 cause a heterogeneous set of conditions ranging from Leber's congenital amaurosis (LCA), the severest form of early-onset retinal degeneration, to milder forms such as retinitis pigmentosa (RP) and cone-rod dystrophy. In mice, null and hypomorphic alleles cause retinal degeneration similar to human LCA and RP, respectively. Thus these mouse models represent two ends of the disease spectrum associated with AIPL1 gene defects in humans. We evaluated whether adeno-associated virus (AAV)-mediated gene replacement therapy in these models could restore PDE biosynthesis in rods and cones and thereby improve photoreceptor survival. We validated the efficacy of human AIPL1 (isoform 1) replacement gene controlled by a promoter derived from the human rhodopsin kinase (RK) gene, which is active in both rods and cones. We found substantial and long-term rescue of the disease phenotype as a result of transgene expression. This is the first gene therapy study in which both rods and cones were targeted successfully with a single photoreceptor-specific promoter. We propose that the vector and construct design used in this study could serve as a prototype for a human clinical trial.
芳香烃受体相互作用蛋白样 1（AIPL1）是光感受器磷酸二酯酶（PDE）生物合成所必需的。AIPL1 基因缺陷导致一系列不同的疾病，从最严重的先天性黑蒙（LCA），即最早发生的视网膜变性，到更温和的形式，如色素性视网膜炎（RP）和锥杆营养不良。在小鼠中，缺失和功能低下等位基因分别导致类似于人类 LCA 和 RP 的视网膜变性。因此，这些小鼠模型代表了与人类 AIPL1 基因缺陷相关的疾病谱的两个极端。我们评估了这些模型中的腺相关病毒（AAV）介导的基因替代治疗是否可以恢复视杆和视锥细胞中的 PDE 生物合成，从而改善光感受器的存活。我们验证了由人视紫红质激酶（RK）基因衍生的启动子控制的人 AIPL1（异构体 1）替代基因的疗效，该启动子在视杆和视锥细胞中均活跃。我们发现转基因表达导致疾病表型的大量和长期挽救。这是第一个用单一光感受器特异性启动子成功靶向视杆和视锥细胞的基因治疗研究。我们提出，本研究中使用的载体和构建设计可以作为人类临床试验的原型。
