CLINICAL STUDY FOR THE TREATMENT OF HUMAN PRION DISEASES

克雅氏病是一种进展迅速、无一例外地致命且无法治愈的疾病 神经退行性疾病，平均持续时间约为8个月。除了伴随CJD的认知和运动缺陷，治疗行为和情绪障碍的困难以及其过程的快速性加剧了其悲剧。此外，新变异型克雅氏病（nvCJD）在英格兰的流行引起了人们对世界牛肉供应安全的严重关注;朊病毒可能通过血液传播的可能性导致禁止居住在英格兰的个人捐献血液或组织。发现朊病毒疾病的有效疗法将对人类和经济产生巨大影响。Prusiner博士实验室的最新实验结果表明，在生理浓度下，抗疟疾药物奎纳克林可以永久清除细胞培养物中的异常先验蛋白。已证实的奎纳克林在细胞培养中的功效、其在临床环境中的相对安全性和众所周知的副作用以及CJD的普遍致死性证明奎纳克林作为治疗CJD的直接候选物是合理的。我们提出了一个治疗研究的患者散发性CJD（sCJD）与外消旋奎纳克林。在三年内，90名患者将进入加州大学旧金山分校弗朗西斯科（UCSF）NIH资助的临床研究中心，在那里将确定sCJD的诊断，并在那里患者将进入一个随机，双盲，奎纳克林治疗研究。患者将被分为两个奎纳克林组，高剂量滴定（每日450 mg）和低剂量滴定（每日75 mg）。他们将接受一年的治疗，然后随访至五年研究期结束。奎纳克林的剂量可根据临床恶化或毒性分别增加或减少。生存率将是本临床研究的主要结局指标。 此外，还将使用其他结局指标评估日常生活活动、认知、MRI和EEG。 我们假设高剂量奎纳克林组患者的生存率比低剂量组患者的生存率高，神经系统进展速度慢。在本项目资助（PPG）的第四年，我们希望开始一项新化合物的临床研究，该化合物在本PPG的其他项目中开发，显示出比外消旋奎纳克林更大的疗效。

Creutzfeldt-Jakob disease (CJD) is a rapidly progressive, invariably fatal and untreatable neurodegenerative disease with a mean duration of about eight months. Beyond the debilitating cognitive and motor deficits that accompany CJD, the difficulty in treating behavioral and mood disturbances and the rapidity of its course compound its tragedy. Moreover, an epidemic of new variant CJD (nvCJD) in England has raised serious concerns regarding the safety of the world's beef supply; the possibility that prions might be passed through the blood has led to the banning of blood or tissue donations from individuals who have resided in England. The discovery of an effective therapy for prion diseases would have enormous human and economic implications. Recent results from experiments in Dr. Prusiner's laboratory show that, at physiological concentrations, the anti-malarial drug quinacrine permanently clears abnormal priori proteins from cell culture. The demonstrated efficacy of quinacrine in cell culture, its relative safety and well known side-effects in the clinical setting, and the universal fatality of CJD justify quinacrine as an immediate candidate for the treatment of CJD. We propose a treatment study for patients with sporadic CJD (sCJD) with racemic quinacrine. Over three years, 90 patients will be admitted to the University of California at San Francisco (UCSF) NIH-funded clinical research center where a diagnosis of sCJD will be determined and where patients will enter into a randomized, double-blinded, treatment study with quinacrine. Patients will be divided into two quinacrine arms, a high-dose titration (450 mg daily) and a low-dose titration (75 mg daily). They will be treated for one year and then be followed through to the end of the five-year study period. The dose of quinacrine may be increased or decreased in each patient depending on clinical deterioration or toxicity, respectively. Survival will be the primary outcome measure of this clinical study. Also, additional outcome measures will be used that assess activities of daily living, cognition, MRI and EEG. We hypothesize that patients in the high-dose quinacrine arm will have increased survival and a slower rate of neurological progression compared with patients in the low dose arm. By year four of this program project grant (PPG), we hope to begin a clinical study with a new compound, developed in other Projects in this PPG, that shows even greater efficacy than racemic quinacrine.