Disease-modifying therapies in PSP

This research team in Marburg, Germany is one of the best in the PSP community. This article reviews “therapeutic approaches aiming at disease-modification rather than mere symptomatic neurotransmitter-replacement therapy.” The two approaches reviewed are agents that target mitochrondrial dysfunction and agents that target tau dysfunction.

This article describes the current state of PSP clinical studies, called “exciting therapeutic developments” by the authors, in the quest for “urgently needed disease-modifying therapies.” The studies are summarized in Table 1 below. I’ve added some notes with a few details I know about these studies.

The abstract and Table 1 are copied below.

A scanned copy of the full article has been posted to the CurePSP website. I’m not sure that’s legal so before anyone figures it out, I suggest you save a copy to your hard-drive if you are interested in the full article. See:

http://psp.org/includes/downloads/stame … eview2.pdf


Here’s the abstract:

Brain. 2010 May 14. [Epub ahead of print]

Rational therapeutic approaches to progressive supranuclear palsy.

Stamelou M, de Silva R, Arias-Carrión O, Boura E, Höllerhage M, Oertel WH, Müller U, Höglinger GU.
Department of Neurology, Philipps University, Marburg, Germany.

Progressive supranuclear palsy is a sporadic and progressive neurodegenerative disease, most often presenting as a symmetric, akinetic-rigid syndrome with postural instability, vertical supranuclear gaze palsy and frontal lobe deficits. It belongs to the family of tauopathies and involves both cortical and subcortical structures.

Although the exact pathophysiology is not yet fully understood, several lines of evidence point to a crucial contribution from both genetic predisposition and mitochondrial dysfunction.

Recently gained insights into the pathophysiology of this disease have led to several hypothesis-driven therapeutic approaches aiming at disease-modification rather than mere symptomatic neurotransmitter-replacement therapy.

Agents targeting mitochondrial dysfunction have already shown a positive effect in a phase II study and further studies to verify and expand these results are ongoing. Clinical studies with agents targeting tau dysfunction such as tau-kinase inhibitors, tau-aggregation inhibitors and microtubule stabilizers are in preparation or ongoing.

This review presents the current pathophysiological concepts driving these exciting therapeutic developments.

PubMed ID#: 20472654 (see pubmed.gov for this abstract only)

This is Table 1, reformatted so it works on the PSP Forum:

Table 1 – Clinical trials aiming at disease modification in PSP

Substance: Coenzyme Q10
Target: Mitochondrial dysfunction
Mechanism: Complex I cofactor
Phase II trial: Significant improvement (Stamelou et al, 2008)
Phase III trial: Recruiting (NCT00382824 on clinicaltrials.gov)
[Robin’s note: This is the study that’s been underway for several years at Lahey Clinic in Boston. It’s now been expanded to include Beth Israel Deaconess Medical Center in Boston and the University of Alabama Birmingham. The last word I had from the study administrator, Stephanie Scala, the dosage for CoQ10 is 2400mg/day.]

Substance: Puruvate, creatine, niacinamide
Target: Mitochondrial dysfunction
Mechanism: Multifunctional cocktail
Phase I trial: Active (NCT00605930 on clinicaltrials.gov)
[Robin’s note: clinical trials spells the first substance as pyruvate]

Substance: Lithium
Target: Tau dysfunction
Mechanism: GSK-3beta inhibitors
Phase I trial: Stopped because of poor tolerability (NCT00703677 on clinicaltrials.gov)
[Robin’s note: Thanks to a local support group member and others on this Forum who participated in this trial.]

Substance: Valproic acid
Target: Tau dysfunction
Mechanism: Aggregation inhibitors
Phase II trial: Active (NCT00385710 on clinicaltrials.gov)

Substance: Nypta
Target: Tau dysfunction
Mechanism: Microtubule stabilizers
Phase II trial: Recruiting (NCT01049399 on clinicaltrials.gov)
[Robin’s note: This trial is now recruiting at at a couple of US institutions, including PMDI in SoCal.]

Substance: Methylthioninium chloride
Target: Tau dysfunction
Mechanism: Microtubule stabilizers
Phase II trial: Significant improvement in Alzheimer’s disease (Wischik et al, 2008); PSP not studied
[Robin’s note: I assume this is Rember.]

Substance: Danuvetide
Target: Tau dysfunction
Mechanism: Microtubule stabilizers
Phase II trial: PSP study in preparation
[Robin’s note: Danuvetide is also called NAP or AL-108. A 12-person pilot study is underway now at UCSF.]