Human prion diseases are etiologically categorized into three forms: sporadic, genetic, and infectious. Sporadic Creutzfeldt-Jakob disease (sCJD) is the most common type of human prion disease that manifests as subacute progressive dementia. No effective therapy for sCJD is currently available. Potential therapeutic compounds are frequently tested in rodents infected with mouse-adapted prions that differ from human prions. However, therapeutic effect varies depending on the prion strain, which is one of the reasons why candidate compounds have shown little effect in sCJD patients. We previously reported that intraperitoneal administration of FK506 was able to prolong the survival of mice infected with a mouse-adapted prion by suppressing the accumulation of abnormal prion protein (PrP) and inhibiting the activation of microglia. In this study, we tested oral administration of FK506 in knock-in mice expressing chimeric human prion protein (KiChM) that were infected with sCJD to determine if this compound is also effective against a clinically relevant human prion, i.e., one that has not been adapted to mice. Treatment with FK506, started either just before or just after disease onset, suppressed typical sCJD pathology (gliosis) and slightly but significantly prolonged the survival of sCJD-inoculated mice. It would be worthwhile to conduct a clinical trial using FK506, which has been safety-approved and is widely used as a mild immunosuppressant.

人类朊病毒病按病因分为三种形式：散发性、遗传性和传染性。散发性克雅氏病 (sCJD) 是最常见的人类朊病毒病，表现为亚急性进行性痴呆。目前尚无治疗 sCJD 的有效疗法。潜在的治疗化合物经常在感染了不同于人类朊病毒的小鼠适应朊病毒的啮齿动物中进行测试。然而，治疗效果因朊病毒株而异，这也是候选化合物对sCJD患者效果甚微的原因之一。我们之前报道过，腹腔注射FK506能够通过抑制异常朊病毒蛋白（PrP）的积累和抑制小胶质细胞的激活来延长感染小鼠适应性朊病毒的小鼠的存活时间。在这项研究中，我们在感染了 sCJD 的表达嵌合人朊病毒蛋白 (KiChM) 的敲入小鼠中测试了 FK506 的口服给药，以确定该化合物是否也能有效对抗临床相关的人朊病毒，即尚未被研究的人朊病毒。适应小鼠。在疾病发作之前或之后开始使用 FK506 治疗，可抑制典型的 sCJD 病理（神经胶质增生），并略微但显着地延长 sCJD 接种小鼠的存活时间。使用 FK506 进行临床试验是值得的，FK506 已获得安全性批准，并作为温和的免疫抑制剂被广泛使用。