Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, Florida, United States of America.
PLoS One. 2012;7(4):e35250. doi: 10.1371/journal.pone.0035250. Epub 2012 Apr 11.
Achromatopsia is a rare autosomal recessive disorder which shows color blindness, severely impaired visual acuity, and extreme sensitivity to bright light. Mutations in the alpha subunits of the cone cyclic nucleotide-gated channels (CNGA3) are responsible for about 1/4 of achromatopsia in the U.S. and Europe. Here, we test whether gene replacement therapy using an AAV5 vector could restore cone-mediated function and arrest cone degeneration in the cpfl5 mouse, a naturally occurring mouse model of achromatopsia with a CNGA3 mutation. We show that gene therapy leads to significant rescue of cone-mediated ERGs, normal visual acuities and contrast sensitivities. Normal expression and outer segment localization of both M- and S-opsins were maintained in treated retinas. The therapeutic effect of treatment lasted for at least 5 months post-injection. This study is the first demonstration of substantial, relatively long-term restoration of cone-mediated light responsiveness and visual behavior in a naturally occurring mouse model of CNGA3 achromatopsia. The results provide the foundation for development of an AAV5-based gene therapy trial for human CNGA3 achromatopsia.
全色盲是一种罕见的常染色体隐性疾病，表现为色盲、严重视力受损和对强光极度敏感。圆锥细胞环核苷酸门控通道（CNGA3）的α亚基突变约占美国和欧洲全色盲的 1/4。在这里，我们测试了使用 AAV5 载体的基因替代疗法是否可以恢复 cpfl5 小鼠中的锥细胞介导功能并阻止锥细胞退化，cpfl5 小鼠是一种具有 CNGA3 突变的天然发生的全色盲小鼠模型。我们表明，基因治疗导致锥细胞介导的 ERG、正常视力和对比敏感度显著恢复。治疗后的视网膜中 M-和 S-视蛋白的正常表达和外节定位得以维持。治疗的治疗效果至少持续了 5 个月。这项研究首次证明了在 CNGA3 全色盲的天然发生小鼠模型中，锥细胞介导的光反应性和视觉行为得到了实质性的、相对长期的恢复。该结果为开发基于 AAV5 的人类 CNGA3 全色盲基因治疗试验提供了基础。
