The Expression Pattern of Systemically Injected AAV9 in the Developing Mouse Retina Is Determined by Age
The Expression Pattern of Systemically Injected AAV9 in the Developing Mouse Retina Is Determined by Age
复制标题
DOI：
10.1038/mt.2014.181
复制
发表时间：
2015-02-01
影响因子：
12.4
通讯作者：
Flannery, John G.
中科院分区：
文献类型：
--
作者：
Byrne, Leah C.;Lin, Yvonne J.;Flannery, John G.
AAV9的全身递送提供了广泛和有效的基因递送到视网膜的潜力，因此可能是治疗眼内注射不可能的疾病、影响多个器官的综合征或需要早期干预的疾病的有用方法。由静脉内注射AAV9产生的表达在新生儿中比在成人中更有效，并且在此我们表征了年龄对小鼠视网膜中AAV9的视网膜转导的影响。我们发现，在新生小鼠中的表达模式与视网膜血管系统的发育相关，并且视网膜转导的区域以及感染的细胞类型根据注射时的年龄而变化。此外，我们证明了连续注射携带两种不同转基因的AAV9载体感染视网膜的相邻区域，提供了更大的覆盖面积。最后，我们表明Mfsd2a（一种与功能性血脑屏障成熟相关的蛋白质）在视网膜中的内源性时空表达模式与静脉内递送的AAV9对视网膜转导的抑制一致，这表明AAV9通过胞吞作用穿过血视网膜屏障。
Systemic delivery of AAV9 offers the potential for widespread and efficient gene delivery to the retina, and may thus be a useful approach for treatment of disease where intraocular injections are not possible, for syndromes affecting multiple organs, or where early intervention is required. The expression resulting from intravenous injection of AAV9 is more efficient in neonates than adults, and here we characterize the effect of age on retinal transduction of AAV9 in the mouse retina. We find that the pattern of expression in neonatal mice is correlated to the development of the retinal vasculature, and that the area of the retinal transduction as well as the cell types infected vary depending on the age at injection. Furthermore, we demonstrate that sequential injections of AAV9 vectors carrying two different transgenes infect adjacent areas of the retina, providing a larger area of coverage. Lastly, we show that the retina's endogenous spatiotemporal expression pattern of Mfsd2a, a protein associated with the maturation of a functional blood brain barrier, coincides with suppression of retinal transduction by intravenously-delivered AAV9, suggesting that AAV9 crosses the blood retina barrier through transcytosis.