Immune biomarker- and microRNA-guided dose escalation phase I clinical study of a RIG-Iigand for the treatment of multiple sclerosis

RIG-配体治疗多发性硬化症的免疫生物标志物和 microRNA 指导的剂量递增 I 期临床研究

• 批准号: 50356335
• 负责人: Professor Dr. Gunther Hartmann
• 金额: --
• 依托单位: Institut für Klinische Chemie und Klinische Pharmakologie
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 财政年份: 2007
• 资助国家: 德国
• 起止时间: 2006-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/50356335?language=en
• 关键词: Immune; biomarker; microRNA; guided; dose

In the first funding period we identified RIG-l-like receptors RLHs (RIG-I and MDA-5) as negative regulators of Th1/Th17 responses and uncovered a protective role of the corresponding ligands in multiple sclerosis. Based on these results we now aim at translating this experimental approach with a synthetic RIG-I ligand into the clinical setting in patients with multiple sclerosis. In preparation of a clinical trial with the synthetic RIG-I ligand we will first evaluate immunological biomarkers and the microRNA profile in the blood of healthy volunteers and of patients with multiple sclerosis receiving routine treatment with a standard dose of IFN-ß. Based on these results we will perform a clinical trial in which healthy volunteers receive increasing doses of RIGI ligand up to the biomarker level established in the first part and under additional guidance by the preclinical in vitro and in vivo results. This stepwise approach will allow to identify a safe and effective dose level (RIG-I ligand is a first in class, first in man, immunological) for subsequent testing of RIG-I ligand in a phase II efficacy trial. For this trial our expectation is that treatment with RIG-I ligand reaches at least the level of therapeutic activity of established IFN-ß treatment or higher.

在第一个资助期，我们鉴定了RIG-I样受体RLH（RIG-I和MDA-5）作为Th 1/Th 17应答的负调节剂，并揭示了相应配体在多发性硬化中的保护作用。基于这些结果，我们现在的目标是将这种合成RIG-I配体的实验方法转化为多发性硬化症患者的临床环境。在用合成RIG-I配体进行临床试验的准备中，我们将首先评估健康志愿者和接受标准剂量IFN-γ常规治疗的多发性硬化症患者血液中的免疫学生物标志物和microRNA谱。基于这些结果，我们将进行一项临床试验，其中健康志愿者接受增加剂量的RIGI配体，直至第一部分中确定的生物标志物水平，并在临床前体外和体内结果的额外指导下。这种逐步的方法将允许确定安全和有效的剂量水平（RIG-I配体是同类中第一种，在人类中第一种，免疫学的），用于随后在II期功效试验中测试RIG-I配体。对于该试验，我们的期望是用RIG-I配体治疗至少达到已建立的IFN-γ治疗的治疗活性水平或更高。