Introduction Progressive supranuclear palsy (PSP) is a progressive neurodegenerative
disease marked by a variety of movement, ocular, and cognitive symptoms. Currently,
treatment is symptomatic, and there are no disease-modulating therapies. While clinical
presentations can be variable, at autopsy, PSP shows 4-repeat (4 R) tau species that
accumulate in brainstem, subcortical, and neocortical areas. Thus, several tau-directed
therapies have been trialed in PSP but with disappointing results to date. Areas Covered
We review PSP clinicopathological correlates and biomarkers and searched clinicaltrials.gov
and pubmed.ncbi.nlm.nih.gov for disease-modulating trials in PSP from the preclinical
stage to clinical stage 3 and reviewed their rationale and results in human trials.
Expert Opinion Factors that may have hampered tau-directed therapies in PSP include
patient selection, intervening in an advanced disease stage, lack of biomarkers for
prodromal diagnosis, outcome measurements, target engagement measures, selection of
specific tau epitopes, and brain penetration of trialed therapies. Coupled with early
intervention, targets upstream of tau accumulation and corresponding cell death may
need to be identified to modulate the disease course. PSP remains a promising disease
to study tau-directed therapies, and several possible targets are being tackled using
novel approaches bringing hope for future success.
