進行性核上性麻痺の新規治療法開発　―どのように臨床試験を成功させるか―

抄録

Progressive supranuclear palsy (PSP) is a disease characterized by the accumulation of tau protein. In general, tau, amyloid, α–synuclein, and TAR DNA binding protein–43, the major pathogenic proteins, coincidently accumulate both intracellularly and extracellularly in the brains of patients with neurodegenerative diseases. However, in PSP, only tau protein is thought to be accumulated. Therefore, two clinical trials using anti–tau antibodies (tilavonemab and gosuranemab) were conducted to target gain of toxic function due to reduced tau protein accumulation, especially extracellular tau protein. However, the antibodies did not demonstrate efficacy. Furthermore, five autopsy cases after treatment showed no suppression of tau protein expression. Since these antibodies recognize the N–terminus of the tau protein, clinical trials are currently underway for anti–tau antibodies that recognize other regions, such as bepranemab. In addition to anti–tau antibodies, antisense oligonucleotides and small–molecule compounds are also being investigated in clinical trials. It is important to select patients early in the disease course for successful clinical trials when developing disease–modifying therapies. We discussed the incorporation of patients in the early stages of disease based on biomarkers and tau positron emission tomography studies to conduct successful clinical trials.