Investigational therapeutics for the treatment of progressive supranuclear palsy

ABSTRACT

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.

KEYWORDS:

• Tauopathy
• progressive supranuclear palsy
• treatment
• immunotherapy
• gene therapy
• biomarkers

Article highlights

• Progressive supranuclear palsy is a 4R tauopathy with a spectrum of clinical presentations.

• Emerging biomarkers may add to the phenotypes that could be enrolled in clinical trials, improve the accuracy in enrolling subjects into trials with PSP, and serve as additional endpoints to augment clinical assessments of disease progression.

• Tau becomes misfolded, aggregates, undergoes several posttranslational modifications, is spread between neurons and glial cells, and leads to cell death in PSP.

• Trials to date targeting these changes including kinase and acetylation inhibitors, microtubule stabilizers, anti-aggregants, antioxidants, and passive immunotherapy have not shown efficacy.

• Newer agents aimed at neuronal and synaptic growth, targeting O-GlcNAc modification, lowering tau by gene therapy or autophagy, and refinements to prior agents are underway.

• Tau immunotherapy targets are shifting from N-terminus to the C-terminal and microtubule-binding region targets

This box summarizes key points contained in the article.

Declaration of interest

David Coughlin MD is supported by the NINDS (NS120038) and serves as an investigator on trials by Novartis, Roche, the Michael J Fox Foundation, and Transposon therapeutics but does not receive support from these entities. Dr. Litvan is supported by the National Institutes of Health grants: 2R01AG038791-06A, U01NS80818, R25NS098999, U19 AG063911-1 and 1R21NS114764-01A1; Parkinson Foundation, Michael J Fox Foundation, Lewy Body Association, CurePSP; AVID Pharmaceuticals, Roche, Abbvie, Biogen, Centogene. EIP-Pharma, Biohaven Pharmaceuticals, Novartis, and United Biopharma SRL - UCB. She receives her salary from the University of California San Diego. She is Chief Editor of Frontiers in Neurology and receives funds as a member of the Advisory Board of the Rossy PSP Center at the University of Toronto.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One reviewer participated in development of a new therapeutic protocole on PSP in France (Alzprotect). Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose

Additional information

Funding

This paper was not funded