Transduction of Photoreceptors With Equine Infectious Anemia Virus Lentiviral Vectors: Safety and Biodistribution of StarGen for Stargardt Disease
Transduction of Photoreceptors With Equine Infectious Anemia Virus Lentiviral Vectors: Safety and Biodistribution of StarGen for Stargardt Disease
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DOI：
10.1167/iovs.13-11871
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发表时间：
2013-06-01
影响因子：
4.4
通讯作者：
Mitrophanous, Kyriacos A.
中科院分区：
文献类型：
--
作者：
Binley, Katie;Widdowson, Peter;Mitrophanous, Kyriacos A.
目的. StarGen是一种基于马传染性贫血病毒（EIAV）的慢病毒载体，表达在Stargardt病（STGD 1）（一种青少年黄斑营养不良）中突变的光受体特异性三磷酸腺苷（ATP）结合盒转运蛋白（ABCA 4）。EIAV载体在视网膜下递送后能够有效地粘附成年猕猴和兔视网膜中的视杆和视锥光感受器以及视网膜色素上皮。评价StarGen在猕猴和兔视网膜下给药后的安全性和生物分布。在两个物种中进行定期眼科检查、IOP测量、ERG反应和组织病理学，以比较对照和载体处理的眼睛。获得组织和液体样品以评价视网膜下递送后载体的持久性、生物分布和脱落。眼科检查显示，与两个种属中对照处理眼相比，StarGen中的炎症水平略高。然而，炎症是一过性的，在StarGen治疗的眼睛中没有观察到明显的毒性，也没有异常的临床结果。在家兔或猕猴中均未发现StarGen相关的IOP升高或异常ERG反应。眼部组织学检查未发现StarGen视网膜下给药导致的任何有害变化。尽管在兔血清中检测到StarGen载体组分的抗体，但在猕猴血清中未检测到，这种免疫应答未导致任何长期毒性。生物分布分析表明StarGen载体仅限于眼区。总之，这些研究证明StarGen在视网膜下给药后耐受性良好且局部化。
PURPOSE. StarGen is an equine infectious anemia virus (EIAV)-based lentiviral vector that expresses the photoreceptor-specific adenosine triphosphate (ATP)-binding cassette transporter (ABCA4) protein that is mutated in Stargardt disease (STGD1), a juvenile macular dystrophy. EIAV vectors are able to efficiently transduce rod and cone photoreceptors in addition to retinal pigment epithelium in the adult macaque and rabbit retina following subretinal delivery. The safety and biodistribution of StarGen following subretinal delivery in macaques and rabbits was assessed.METHODS. Regular ophthalmic examinations, IOP measurements, ERG responses, and histopathology were carried out in both species to compare control and vector-treated eyes. Tissue and fluid samples were obtained to evaluate the persistence, biodistribution, and shedding of the vector following subretinal delivery.RESULTS. Ophthalmic examinations revealed a slightly higher level of inflammation in StarGen compared with control treated eyes in both species. However, inflammation was transient and no overt toxicity was observed in StarGen treated eyes and there were no abnormal clinical findings. There was no StarGen-associated rise in IOP or abnormal ERG response in either rabbits or macaques. Histopathologic examination of the eyes did not reveal any detrimental changes resulting from subretinal administration of StarGen. Although antibodies to StarGen vector components were detected in rabbit but not macaque serum, this immunologic response did not result in any long-term toxicity. Biodistribution analysis demonstrated that the StarGen vector was restricted to the ocular compartment.CONCLUSIONS. In summary, these studies demonstrate StarGen to be well tolerated and localized following subretinal administration.