Safety and Biodistribution of an Equine Infectious Anemia Virus-Based Gene Therapy, RetinoStat®, for Age-Related Macular Degeneration
Safety and Biodistribution of an Equine Infectious Anemia Virus-Based Gene Therapy, RetinoStat®, for Age-Related Macular Degeneration
复制标题
DOI：
10.1089/hum.2012.008
复制
发表时间：
2012-09-01
影响因子：
4.2
通讯作者：
Naylor, Stuart
中科院分区：
文献类型：
--
作者：
Binley, Katie;Widdowson, Peter S.;Naylor, Stuart
RetinoStat (R) 是一种基于马传染性贫血病毒的慢病毒基因治疗载体，表达血管抑制蛋白内皮抑素和血管抑制素，通过视网膜下注射递送，用于治疗湿性年龄相关性黄斑变性。我们在两个物种中启动了为期 6 个月的安全性和生物分布研究；恒河猴和荷兰带兔。视网膜下施用 RetinoStat 后，接受治疗的兔眼玻璃体中的人内皮抑素和血管抑素蛋白水平在给药后约 1 个月达到峰值，并在研究期间保持升高状态。定期眼部检查显示，两种物种均存在轻度至中度短暂性眼部炎症，该炎症在给药后 1 个月内消退。与 RetinoStat 治疗眼睛的基线读数相比，给药后兔子或猕猴的视网膜电图或眼压测量值没有显着的长期变化。尽管玻璃体、视网膜和脉络膜中有单核细胞浸润，但组织学评估并未显示眼睛有任何结构变化。在任一物种的血清中均未检测到针对任何 RetinoStat 载体成分或转基因的抗体，生物分布分析表明 RetinoStat 载体保留在眼室内。总之，这些研究发现 RetinoStat 具有良好的耐受性、局部性，并且能够在视网膜下递送后持续表达。
RetinoStat (R) is an equine infectious anemia virus-based lentiviral gene therapy vector that expresses the angiostatic proteins endostatin and angiostatin that is delivered via a subretinal injection for the treatment of the wet form of age-related macular degeneration. We initiated 6-month safety and biodistribution studies in two species; rhesus macaques and Dutch belted rabbits. After subretinal administration of RetinoStat the level of human endostatin and angiostatin proteins in the vitreous of treated rabbit eyes peaked at similar to 1 month after dosing and remained elevated for the duration of the study. Regular ocular examinations revealed a mild to moderate transient ocular inflammation that resolved within 1 month of dosing in both species. There were no significant long-term changes in the electroretinograms or intraocular pressure measurements in either rabbits or macaques postdosing compared with the baseline reading in RetinoStat-treated eyes. Histological evaluation did not reveal any structural changes in the eye although there was an infiltration of mononuclear cells in the vitreous, retina, and choroid. No antibodies to any of the RetinoStat vector components or the transgenes could be detected in the serum from either species, and biodistribution analysis demonstrated that the RetinoStat vector was maintained within the ocular compartment. In summary, these studies found RetinoStat to be well tolerated, localized, and capable of persistent expression after subretinal delivery.