Ocular toxicity, distribution, and shedding of intravitreal AAV-eqIL-10 in horses.

IF 4.6 2区医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL

Molecular Therapy-Methods & Clinical Development Pub Date : 2024-10-28 eCollection Date: 2024-12-12 DOI:10.1016/j.omtm.2024.101360

Kim Young, Tomoko Hasegawa, Naveen Vridhachalam, Nichol Henderson, Jacklyn H Salmon, Trace F McCall, Matthew L Hirsch, Brian C Gilger

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引用次数: 0

Abstract

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.

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视网膜内 AAV-eqIL-10 对马眼部的毒性、分布和脱落。

非传染性葡萄膜炎（NIU）是一种痛苦的复发性疾病，影响了2%-5%的马。目前的治疗需要频繁给药，并伴有相关的不良事件。在之前的一项研究中，玻璃体内（IVT）腺相关病毒（AAV）携带马白细胞介素-10 (eqIL-10) cDNA抑制实验性大鼠葡萄膜炎。本研究的目的是评估正常马IVT注射AAV8-eqIL-10后的眼耐受性、载体基因组（vg）分布和载体脱落，并假设它在马体内具有剂量依赖性的良好耐受性。注射耐受性良好，有轻微的短暂性眼部炎症症状；然而，接受最高剂量的马出现了角状沉淀。注射后3天泪液、尿液、粪便中均未检测到vgs。水溶液和玻璃体中eqIL-10水平高于1.5 ng/mL，比报道的有效内源性和诱导水平高出20倍以上。vgs在眼部组织中检测到，全身分布仅在肝脏和肾脏中发现。给药后86天未发现全身效应。进一步研究低剂量的IVT AAV8-eqIL-10治疗是迈向安全有效的马葡萄膜炎单剂量治疗的重要一步，对治疗人类NIU具有更广泛的意义。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Therapy-Methods & Clinical Development Biochemistry, Genetics and Molecular Biology-Molecular Biology

CiteScore

9.90

自引率

4.30%

发文量

163

审稿时长

12 weeks

期刊介绍： The aim of Molecular Therapy—Methods & Clinical Development is to build upon the success of Molecular Therapy in publishing important peer-reviewed methods and procedures, as well as translational advances in the broad array of fields under the molecular therapy umbrella. Topics of particular interest within the journal''s scope include: Gene vector engineering and production, Methods for targeted genome editing and engineering, Methods and technology development for cell reprogramming and directed differentiation of pluripotent cells, Methods for gene and cell vector delivery, Development of biomaterials and nanoparticles for applications in gene and cell therapy and regenerative medicine, Analysis of gene and cell vector biodistribution and tracking, Pharmacology/toxicology studies of new and next-generation vectors, Methods for cell isolation, engineering, culture, expansion, and transplantation, Cell processing, storage, and banking for therapeutic application, Preclinical and QC/QA assay development, Translational and clinical scale-up and Good Manufacturing procedures and process development, Clinical protocol development, Computational and bioinformatic methods for analysis, modeling, or visualization of biological data, Negotiating the regulatory approval process and obtaining such approval for clinical trials.