Broad Institute of Harvard and MIT, Cambridge, MA, USA; Department of Neurology, and Henry and Allison McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA, USA.
Broad Institute of Harvard and MIT, Cambridge, MA, USA; Department of Neurology, and Henry and Allison McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA, USA.
Lancet Neurol. 2020 Apr;19(4):361-368. doi: 10.1016/S1474-4422(19)30403-X. Epub 2020 Mar 18.
Prion disease is a rare, fatal, and exceptionally rapid neurodegenerative disease. Although incurable, prion disease follows a clear pathogenic mechanism, in which a single gene gives rise to a single prion protein (PrP) capable of converting into the sole causal disease agent, the misfolded prion. As efforts progress to leverage this mechanistic knowledge toward rational therapies, a principal challenge will be the design of clinical trials. Previous trials in prion disease have been done in symptomatic patients who are often profoundly debilitated at enrolment. About 15% of prion disease cases are genetic, creating an opportunity for early therapeutic intervention to delay or prevent disease. Highly variable age of onset and absence of established prodromal biomarkers might render infeasible existing models for testing drugs before disease onset. Advancement of near-term targeted therapeutics could crucially depend on thoughtful design of rigorous presymptomatic trials.
朊病毒病是一种罕见、致命且异常迅速的神经退行性疾病。尽管无法治愈，但朊病毒病遵循明确的发病机制，即单一基因产生单一朊病毒蛋白（PrP），该蛋白能够转化为唯一的致病因子，即错误折叠的朊病毒。随着人们努力利用这一机制知识开发合理的治疗方法，一个主要的挑战将是临床试验的设计。先前在朊病毒病中的试验是在症状出现的患者中进行的，这些患者在入组时往往已经极度虚弱。大约 15%的朊病毒病是遗传性的，这为早期治疗干预以延迟或预防疾病提供了机会。发病年龄高度可变，且缺乏明确的前驱生物标志物，这可能使得在疾病发作前测试药物的现有模型不可行。近期靶向治疗的进展可能极大地取决于严格的无症状前临床试验的精心设计。
