Avrutsky Maria I, Chen Claire W, Lawson Jacqueline M, Snipas Scott J, Salvesen Guy S, Troy Carol M
Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, United States.
NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United States.
Front Neurosci. 2023 Jun 28;17:1209527. doi: 10.3389/fnins.2023.1209527. eCollection 2023.
Retinal vein occlusion (RVO) is a sight-threatening condition typically treated with intravitreal injection of vascular endothelial growth factor (VEGF) antagonists. Treatment response to anti-VEGF therapies is highly variable, with poor visual outcomes and treatment response in patients with significant retinal nonperfusion following RVO. Recently, caspase-9 has been identified as a potent regulator of edema, gliosis, and neuronal dysfunction during acute retinal hypoxia. The purpose of this study was to compare the therapeutic effect of caspase-9 inhibition against VEGF-neutralization in an established mouse model of RVO.
Adult male C57Bl/6 J mice were randomized to induction of RVO and treatment with either vehicle, intravitreal injection of anti-VEGF antibody, topical administration of a selective caspase-9 inhibitor (Pen1-XBir3), or a combination therapy. Animals were followed on days 1, 2, and 8 after RVO with fundus retinal imaging, and with optical coherence tomography (OCT) to capture retinal swelling, capillary nonperfusion (measured by disorganization of retinal inner layers, DRIL), hyperreflective foci (HRF), and retinal atrophy. Focal electroretinography (ERG) measurements were performed on day 7. Histology was performed on retinal sections from day 8.
Both VEGF neutralization and caspase-9 inhibition showed significant retinal protection from RVO compared to vehicle treatment arm. Retinal reperfusion of occluded veins was accelerated in eyes receiving caspase-9 inhibitor, but not significantly different from vehicle in the anti-VEGF group. Retinal edema was suppressed in all treatment groups, with approximately 2-fold greater edema reduction with caspase-9 inhibition compared to VEGF neutralization. HRF were reduced similarly across all treatment groups compared to vehicle. Retinal detachment was reduced only in eyes treated with caspase-9 inhibitor monotherapy. Caspase-9 inhibition reduced retinal atrophy and preserved ERG response; VEGF neutralization did not prevent neurodegeneration following RVO.
Caspase-9 inhibition confers stronger neuronal and vascular protection compared to VEGF neutralization in the mouse laser-induced model of RVO.
视网膜静脉阻塞（RVO）是一种威胁视力的疾病，通常通过玻璃体内注射血管内皮生长因子（VEGF）拮抗剂进行治疗。抗VEGF治疗的反应高度可变，RVO后视网膜显著无灌注的患者视觉预后和治疗反应较差。最近，半胱天冬酶-9已被确定为急性视网膜缺氧期间水肿、胶质增生和神经元功能障碍的有效调节因子。本研究的目的是在已建立的RVO小鼠模型中比较半胱天冬酶-9抑制与VEGF中和的治疗效果。
将成年雄性C57Bl/6 J小鼠随机分为RVO诱导组，并分别接受载体治疗、玻璃体内注射抗VEGF抗体、局部给予选择性半胱天冬酶-9抑制剂（Pen1-XBir3）或联合治疗。在RVO后的第1、2和8天，通过眼底视网膜成像以及光学相干断层扫描（OCT）对动物进行随访，以观察视网膜肿胀、毛细血管无灌注（通过视网膜内层紊乱测量，DRIL）、高反射灶（HRF）和视网膜萎缩情况。在第7天进行局部视网膜电图（ERG）测量。在第8天对视网膜切片进行组织学检查。
与载体治疗组相比，VEGF中和和半胱天冬酶-9抑制均显示出对RVO的显著视网膜保护作用。接受半胱天冬酶-9抑制剂治疗的眼睛中阻塞静脉的视网膜再灌注加速，但与抗VEGF组的载体治疗组无显著差异。所有治疗组的视网膜水肿均得到抑制，与VEGF中和相比，半胱天冬酶-9抑制使水肿减少约2倍。与载体治疗组相比，所有治疗组的HRF均有类似程度的降低。仅在接受半胱天冬酶-9抑制剂单一疗法治疗的眼睛中视网膜脱离减少。半胱天冬酶-9抑制减少了视网膜萎缩并保留了ERG反应；VEGF中和未能预防RVO后的神经退行性变。
在小鼠激光诱导的RVO模型中，与VEGF中和相比，半胱天冬酶-9抑制具有更强的神经元和血管保护作用。
