Young Kim, Hasegawa Tomoko, Vridhachalam Naveen, Henderson Nichol, Salmon Jacklyn H, McCall Trace F, Hirsch Matthew L, Gilger Brian C
Clinical Sciences, North Carolina State University, Raleigh, NC 27607, USA.
Ophthalmology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
Mol Ther Methods Clin Dev. 2024 Oct 28;32(4):101360. doi: 10.1016/j.omtm.2024.101360. eCollection 2024 Dec 12.
Non-infectious uveitis (NIU) is a painful recurrent disease affecting 2%-5% of horses. Current treatments require frequent administration with associated adverse events. In a previous study, intravitreal (IVT) adeno-associated virus (AAV) harboring equine interleukin-10 (eqIL-10) cDNA inhibited experimental uveitis in rats. The goal of this study was to evaluate the ocular tolerability, vector genome (vg) distribution, and vector shedding following an IVT injection of AAV8-eqIL-10 in normal horses with the hypothesis that it would be well tolerated in a dose-dependent manner in horses. Injections were well tolerated with mild transient signs of ocular inflammation; however, horses receiving the highest dose developed keratic precipitates. The vgs were not detected in the tears 3 days after injection, or in urine or feces at any time. Aqueous and vitreous humor eqIL-10 levels increased to higher than 1.5 ng/mL, more than 20 times higher than reported effective endogenous and induced levels. The vgs were detected in ocular tissues, and systemic distribution was identified only in the liver and kidney. No systemic effects were identified 86 days after dosing with IVT AAV-eqIL-10. Further investigation of lower doses of IVT AAV8-eqIL-10 therapy is an important next step toward a safe and effective single-dose treatment of equine uveitis with broader implications for treating NIU in humans.
非感染性葡萄膜炎（NIU）是一种影响2%-5%马匹的复发性疼痛疾病。目前的治疗方法需要频繁给药且伴有不良事件。在之前的一项研究中，携带马白细胞介素-10（eqIL-10）cDNA的玻璃体内（IVT）腺相关病毒（AAV）抑制了大鼠的实验性葡萄膜炎。本研究的目的是评估在正常马匹中玻璃体内注射AAV8-eqIL-10后的眼耐受性、载体基因组（vg）分布和载体脱落情况，假设其在马匹中会以剂量依赖的方式被良好耐受。注射耐受性良好，仅有轻微短暂的眼部炎症迹象；然而，接受最高剂量的马匹出现了角膜后沉着物。注射后3天在泪液中未检测到vg，在尿液或粪便中任何时候都未检测到。房水和玻璃体液中eqIL-10水平升高至高于1.5 ng/mL，比报道的有效内源性和诱导水平高出20倍以上。在眼组织中检测到了vg，仅在肝脏和肾脏中发现了全身分布。玻璃体内注射AAV-eqIL-10给药86天后未发现全身影响。进一步研究较低剂量的玻璃体内AAV8-eqIL-10治疗是朝着安全有效的单剂量治疗马葡萄膜炎迈出的重要下一步，对治疗人类NIU具有更广泛的意义。
