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

Abstract

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.

Frontrunner in Translation: Progressive Supranuclear Palsy

“…BIIB092 is directed to an N-terminally truncated form of extracellular tau. These agents showed no significant adverse events in the phase I trials and are being well-tolerated in ongoing phase II studies (140, 239). Unfortunately, ABBV-8E12 trial was recently discontinued due to lack of benefit.…”

“…However, the GSK3 inhibitors (including lithium, sodium valproate, and tideglusib) recently evaluated in clinical therapeutic trials of PSP patients failed to slow disease progression (138, 139). Other kinases and phosphatases are under evaluation (140). However, it is not yet known whether tau hyperphosphorylation is a cause for or a consequence of tau aggregation.…”

“…Davunetide, a neuroprotective and microtubule stabilizer, was evaluated with the same negative results (233). However, other phosphorylation inhibitors, microtubule stabilizers and neuroprotective agents are still under evaluation (140). Mitochondrial function enhancing nutrients including coenzyme Q10 have also been tested in clinical trials of PSP patients with no apparent benefit (140, 165).…”

One decade ago, one decade ahead in progressive supranuclear palsy

“…The latest knowledge about transcellular spread of tau species with prion‐like properties could lead to novel therapeutic approaches for PSP. Indeed, active or passive immunization aiming to reduce tau levels extracellularly has already shown encouraging experimental results . Two such phase II studies of passive tau immunization in PSP are currently ongoing and seem promising.…”

“…Indeed, active or passive immunization aiming to reduce tau levels extracellularly has already shown encouraging experimental results. 98 Two such phase II studies of passive tau immunization in PSP are currently ongoing and seem promising.…”