Alexander John J, Hauswirth William W
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida, USA.
Drug News Perspect. 2008 Jun;21(5):267-71. doi: 10.1358/dnp.2008.21.5.1219012.
Gene therapy strategies that target therapeutic genes to retinal cones are a worthy goal both because cone photoreceptor diseases are severely vision limiting and because many retinal diseases that do not affect cones directly eventually lead to cone loss, the reason for eventual blindness. Human achromatopsia is a genetic disease of cones that renders them nonfunctional but otherwise intact. Thus, animal models of achromatopsia were used in conjunction with adeno-associated virus (AAV) vectors whose serotype efficiently transduces cones and with a promoter that limits transgene expression to cones. In the Gnat2(cpfl3) mouse model of one genetic form of human achromatopsia, we were able to demonstrate recovery of normal cone function and visual acuity after a single subretinal treatment of vector that supplied wild-type Gnat2 protein to cones. This validates the overall strategy of targeting cones using recombinant viral vectors and justifies a more complete examination of animal models of cone disease as a prelude to considering a clinical gene therapy trial.
将治疗性基因靶向视网膜视锥细胞的基因治疗策略是一个有价值的目标，这既是因为视锥光感受器疾病严重限制视力，也是因为许多不直接影响视锥细胞的视网膜疾病最终会导致视锥细胞丧失，这是最终导致失明的原因。人类全色盲是一种视锥细胞的遗传性疾病，它使视锥细胞失去功能，但其他方面保持完整。因此，全色盲动物模型与腺相关病毒（AAV）载体联合使用，该载体的血清型能有效地转导视锥细胞，并与一个将转基因表达限制在视锥细胞的启动子一起使用。在人类一种遗传性全色盲的Gnat2（cpfl3）小鼠模型中，我们能够证明在对视锥细胞单次视网膜下注射提供野生型Gnat2蛋白的载体后，视锥细胞功能和视力恢复正常。这验证了使用重组病毒载体靶向视锥细胞的总体策略，并证明在考虑进行临床基因治疗试验之前，更全面地研究视锥细胞疾病动物模型是合理的。
