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

在第一个资助期，我们确定RIG-L样受体RLHs(RIG-I和MDA5)是Th1/Th17反应的负调节因子，并发现了相应的配体在多发性硬化症中的保护作用。基于这些结果，我们现在的目标是将这种带有合成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。在准备使用合成RIG-I配体进行临床试验时，我们将首先评估健康志愿者和接受标准剂量干扰素常规治疗的多发性硬化症患者血液中的免疫生物标记物和microRNA图谱。基于这些结果，我们将进行一项临床试验，在临床前、体外和体内结果的指导下，健康志愿者接受剂量增加的RIGI配体，直到第一部分中确定的生物标记物水平。这种循序渐进的方法将允许确定安全和有效的剂量水平(RIG-I配体是一流的，人类第一的，免疫学的)，用于在II期疗效试验中随后对RIG-I配体进行测试。对于这项试验，我们的期望是RIG-I配体的治疗至少达到已有的干扰素治疗的治疗活性水平或更高。

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.