Investigational therapeutics for the treatment of progressive supranuclear palsy

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.

Automated summary

This article reviews the clinicopathological correlates and biomarkers of PSP and the progress of disease-modulating therapies for PSP. Experts believe that various factors, including patient selection, treatment timing, lack of biomarkers for prodromal diagnosis, and brain penetration of therapies, have hindered the success of tau-directed therapies in PSP. Coupled with early intervention, targeting upstream factors of tau accumulation and cell death may be necessary to modulate the disease course.