Preclinical, phase I, and phase II investigational clinical trials for treatment of progressive supranuclear palsy

ABSTRACT

Introduction: Our understanding of the pathological basis of progressive supranuclear palsy (PSP), as the most common atypical parkinsonian syndrome, has greatly increased in recent years and a number of disease-modifying therapies are under evaluation as a result of these advances.

Areas covered: In this review, we discuss disease-modifying therapeutic options which are currently under evaluation or have been evaluated in preclinical or clinical trials based on their targeted pathophysiologic process. The pathophysiologic mechanisms are broadly divided into three main categories: genetic mechanisms, abnormal post-translational modifications of tau protein, and transcellular tau spread.

Expert opinion: Once the best therapeutic approaches are identified, it is likely that some combination of interventions will need to be evaluated, but this will take time. It is critical to treat patients at early stages, and development of the Movement Disorder Society PSP diagnostic criteria is an important step in this direction. In addition, development of biological biomarkers such as tau PET and further refinement of tau ligands may help both diagnose early and measure disease progression. In the meantime, a comprehensive, personalized interdisciplinary approach to this disease is absolutely necessary.

KEYWORDS:

• Progressive supranuclear palsy
• neurodegenerative disorder
• tauopathy
• clinical trial

Article highlights

• Progressive supranuclear palsy is the most common primary tauopathy and atypical parkinsonian disorder. The effect of current treatments for PSP have usually been at best marginal, transient, and without modification in the course of the disease progression.

• Current investigational treatments are directed to three pathogenetic mechanisms of the disease including genetic mechanisms, abnormal post-translational modifications of tau protein, and transcellular spread of tau pathology.

• Antisense oligonucleotides as well as anti-tau antibodies/vaccine are the most promising therapeutic options under investigation considering their success in other proteinopathies.

• To allow better design of future clinical trials it is essential to identify diagnostic biomarkers to diagnose PSP early and to measure disease progression accurately.

Declaration of interest

I Litvan is a member of the Biotie/Parkinson Study Group Medical Advisory Board. She is an investigator in NIH Grants: 5P50AG005131-31, 5T35HL007491, 1U01NS086659, and 1U54NS092089-01; Parkinson Study Group, Michael J Fox Foundation, AVID Pharmaceuticals, Abbvie/C2N Diagnostics and Biogen/Bristol-Myers Squibb studies. 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 apart from those disclosed. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper is not funded.