Tau-Centric Targets and Drugs in Clinical Development for the Treatment of Alzheimer's Disease

Francesco Panza, Vincenzo Solfrizzi, Davide Seripa, Bruno P. Imbimbo, Madia Lozupone, Andrea Santamato, Chiara Zecca, Maria Rosaria Barulli, Antonello Bellomo, Alberto Pilotto, Antonio Daniele, Antonio Greco, Giancarlo Logroscino

Research output: Contribution to journalReview articlepeer-review

Abstract

The failure of several Phase II/III clinical trials in Alzheimer's disease (AD) with drugs targeting β-amyloid accumulation in the brain fuelled an increasing interest in alternative treatments against tau pathology, including approaches targeting tau phosphatases/kinases, active and passive immunization, and anti-tau aggregation. The most advanced tau aggregation inhibitor (TAI) is methylthioninium (MT), a drug existing in equilibrium between a reduced (leuco-methylthioninium) and oxidized form (MT+). MT chloride (methylene blue) was investigated in a 24-week Phase II clinical trial in 321 patients with mild to moderate AD that failed to show significant positive effects in mild AD patients, although long-term observations (50 weeks) and biomarker studies suggested possible benefit. The dose of 138 mg/day showed potential benefits on cognitive performance of moderately affected AD patients and cerebral blood flow in mildly affected patients. Further clinical evidence will come from the large ongoing Phase III trials for the treatment of AD and the behavioral variant of frontotemporal dementia on a new form of this TAI, more bioavailable and less toxic at higher doses, called TRx0237. More recently, inhibitors of tau acetylation are being actively pursued based on impressive results in animal studies obtained by salsalate, a clinically used derivative of salicylic acid.

Original languageEnglish
Article number3245935
JournalBioMed Research International
Volume2016
DOIs
Publication statusPublished - 2016

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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