Objective

Inflammatory hand arthritis (IHA) results in impaired function. Local gene therapy with ART-I02, a recombinant adeno-associated virus (AAV) serotype 5 vector expressing interferon (IFN)-β, under the transcriptional control of nuclear factor κ-B responsive promoter, was preclinically shown to have favorable effects. This study aimed to investigate the safety and tolerability of local gene therapy with ART-I02 in patients with IHA.

Methods

In this first-in-human, dose-escalating, cohort study, 12 IHA patients were to receive a single intra-articular (IA) injection of ART-I02 ranging 0.3 × 10¹²-1.2 × 10¹³ genome copies in an affected hand joint. Adverse events (AEs), routine safety laboratory and the clinical course of disease were periodically evaluated. Baseline- and follow-up contrast enhanced magnetic resonance images (MRIs), shedding of viral vectors in bodily fluids, and AAV5 and IFN-β immune responses were evaluated. A data review committee provided safety recommendations.

Results

Four patients were enrolled. Long-lasting local AEs were observed in 3 patients upon IA injection of ART-I02. The AEs were moderate in severity and could be treated conservative. Given the duration of the AEs and their possible or probable relation to ART-I02, no additional patients were enrolled. No systemic treatment emergent AEs were observed. The MRIs reflected the AEs by (peri)arthritis. No T-cell response against AAV5 or IFN-β, nor IFN-β antibodies could be detected. Neutralizing antibody titers against AAV5 raised post-dose.

Conclusion

Single IA doses of 0.6 × 10¹² or 1.2 × 10¹² ART-I02 vector genomes were administered without systemic side effects or serious AEs. However, local tolerability was insufficient for continuation.

Trial registration

NCT02727764.

中文翻译：

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I/II 期研究结果在炎症性手关节炎患者中施用表达干扰素-β 的腺相关病毒载体

客观的

炎症性手关节炎 (IHA) 会导致功能受损。ART-I02 是一种表达干扰素 (IFN)-β 的重组腺相关病毒 (AAV) 血清型 5 载体，在核因子 κ-B 响应启动子的转录控制下进行局部基因治疗，临床前显示具有良好的效果。本研究旨在调查 ART-I02 局部基因治疗在 IHA 患者中的安全性和耐受性。

方法

在这项首次人体、剂量递增的队列研究中，12 名 IHA 患者将在受影响的手部接受单次关节内 (IA) ART-I02 注射，范围为 0.3 × 10 ¹² -1.2 × 10 ^{13 个}基因组拷贝联合的。定期评估不良事件 (AE)、常规安全实验室和临床病程。评估了基线和后续对比增强磁共振图像 (MRI)、体液中病毒载体的脱落以及 AAV5 和 IFN-β 免疫反应。数据审查委员会提供了安全建议。

结果

招募了四名患者。IA 注射 ART-I02 后，在 3 名患者中观察到持久的局部 AE。AE 的严重程度中等，可以保守治疗。鉴于 AE 的持续时间及其与 ART-I02 的可能或可能关系，没有招募更多患者。未观察到系统性治疗出现的 AE。MRI 反映了（周围）关节炎的 AE。没有检测到针对 AAV5 或 IFN-β 的 T 细胞反应，也没有检测到 IFN-β 抗体。针对 AAV5 的中和抗体滴度在给药后升高。

结论

^{给予 0.6 × 10 12}或 1.2 × 10 ¹² ART-I02 载体基因组的单次 IA 剂量，没有全身副作用或严重的 AE。然而，局部耐受性不足以继续。

试用注册

NCT02727764。