Gootwine Elisha, Ofri Ron, Banin Eyal, Obolensky Alexey, Averbukh Edward, Ezra-Elia Raaya, Ross Maya, Honig Hen, Rosov Alexander, Yamin Esther, Ye Guo-Jie, Knop David R, Robinson Paulette M, Chulay Jeffrey D, Shearman Mark S
1 Agricultural Research Organization, The Volcani Center , Rishon LeZion, Israel .
2 Koret School of Veterinary Medicine, Hebrew University of Jerusalem , Rehovot, Israel .
Hum Gene Ther Clin Dev. 2017 Jun;28(2):96-107. doi: 10.1089/humc.2017.028. Epub 2017 May 5.
Applied Genetic Technologies Corporation (AGTC) is developing a recombinant adeno-associated virus (rAAV) vector expressing the human CNGA3 gene designated AGTC-402 (rAAV2tYF-PR1.7-hCNGA3) for the treatment of achromatopsia, an inherited retinal disorder characterized by markedly reduced visual acuity, extreme light sensitivity, and absence of color discrimination. The results are herein reported of a study evaluating safety and efficacy of AGTC-402 in CNGA3-deficient sheep. Thirteen day-blind sheep divided into three groups of four or five animals each received a subretinal injection of an AAV vector expressing a CNGA3 gene in a volume of 500 μL in the right eye. Two groups (n = 9) received either a lower or higher dose of the AGTC-402 vector, and one efficacy control group (n = 4) received a vector similar in design to one previously shown to rescue cone photoreceptor responses in the day-blind sheep model (rAAV5-PR2.1-hCNGA3). The left eye of each animal received a subretinal injection of 500 μL of vehicle (n = 4) or was untreated (n = 9). Subretinal injections were generally well tolerated and not associated with systemic toxicity. Most animals had mild to moderate conjunctival hyperemia, chemosis, and subconjunctival hemorrhage immediately after surgery that generally resolved by postoperative day 7. Two animals treated with the higher dose of AGTC-402 and three of the efficacy control group animals had microscopic findings of outer retinal atrophy with or without inflammatory cells in the retina and choroid that were procedural and/or test-article related. All vector-treated eyes showed improved cone-mediated electroretinography responses with no change in rod-mediated electroretinography responses. Behavioral maze testing under photopic conditions showed significantly improved navigation times and reduced numbers of obstacle collisions in all vector-treated eyes compared to their contralateral control eyes or pre-dose results in the treated eyes. These results support the use of AGTC-402 in clinical studies in patients with achromatopsia caused by CNGA3 mutations, with careful evaluation for possible inflammatory and/or toxic effects.
应用基因技术公司（AGTC）正在研发一种表达人CNGA3基因的重组腺相关病毒（rAAV）载体，名为AGTC - 402（rAAV2tYF - PR1.7 - hCNGA3），用于治疗全色盲，这是一种遗传性视网膜疾病，其特征为视力显著下降、对光极度敏感以及无法辨别颜色。本文报告了一项评估AGTC - 402在CNGA3缺陷绵羊中的安全性和有效性的研究结果。13只日盲绵羊被分为三组，每组四或五只动物，右眼接受500μL表达CNGA3基因的AAV载体的视网膜下注射。两组（n = 9）接受较低或较高剂量的AGTC - 402载体，一个疗效对照组（n = 4）接受一种设计与先前在日盲绵羊模型中显示可挽救视锥光感受器反应的载体相似的载体（rAAV5 - PR2.1 - hCNGA3）。每只动物的左眼接受500μL载体的视网膜下注射（n = 4）或不进行治疗（n = 9）。视网膜下注射一般耐受性良好，且与全身毒性无关。大多数动物在手术后立即出现轻度至中度结膜充血、水肿和结膜下出血，这些症状通常在术后第7天消退。两只接受较高剂量AGTC - 402治疗的动物以及疗效对照组的三只动物在显微镜下发现有视网膜外层萎缩，视网膜和脉络膜中有或没有炎症细胞，这些与手术操作和/或受试药物有关。所有接受载体治疗的眼睛视锥介导的视网膜电图反应均有所改善，而视杆介导的视网膜电图反应没有变化。在明视觉条件下的行为迷宫测试显示，与对侧对照眼或受试眼给药前的结果相比，所有接受载体治疗的眼睛的导航时间显著缩短，障碍物碰撞次数减少。这些结果支持在由CNGA3突变引起的全色盲患者的临床研究中使用AGTC - 402，但需仔细评估可能的炎症和/或毒性作用。
