Dieter, Forschungszentrum Jülich
Oligomeric amyloid β (Aβ) is suspected to be the most toxic species in Aβ aggregation and to be responsible for development and progression of Alzheimer’s disease (AD). Thus, the development of compounds that are able to eliminate already formed, toxic Aβ oligomers is very desirable. In the recent years, we have developed all-D-enantiomeric peptides that have proven to be able to directly and specifically eliminate toxic Aβ oligomers in vitro. The in vivo proof of concept for “D3”, the lead compound of this development, was accomplished in several treatment studies [1-4]. Here, we describe in vivo efficacy of the improved D3 derivative “rational design 2” (RD2), also called “PRI-002” [5-7]. PRI-002 was able to reverse cognitive deficits and to significantly reduce Aβ pathology even after oral administration in old-aged transgenic AD mice with full blown pathology and deficits. For the first time, we demonstrate in vivo target engagement of PRI-002, in particular by showing a significant reduction of Aβ oligomers in the brains of PRI-002 -treated compared to placebo-treated mice. The correlation of Aβ elimination in vivo and the reversal of cognitive deficits in old-aged transgenic mice are in support of Aβ oligomers being relevant not only for disease development and progression, but also for Aβ oligomers as a promising target for the causal treatment of AD. SHIRPA and Rotarod assays were used to follow neurodegeneration in the TBA2.1 mouse model and its successful deceleration by oral treatment with the compound PRI-002. I will summerize preclinical efficiency data with successful in vivo proof-of-concept in four treatment studies in three different transgenic animal models in three different laboratories. Preclinical safety and toxicology data are very favourable. Therefore, we are just about to start a first-in-human phase I clinical trial to show safety also in humans. I will report on the clinical data from the SAD part of the phase I clinical trial.
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Dieter Willbold studied biochemistry in Tübingen (Germany), Bayreuth (Germany) and Boulder (Colorado, USA). He completed his PhD in 1994 at the University of Bayreuth. After some more years in Bayreuth and a couple of research visits, e.g. at the Sackler School of Medicine of the Tel-Aviv University, he headed a junior research group at the Institute of Molecular Biotechnology in Jena. In 2001 Willbold became an associate professor at the Heinrich-Heine-University of Düsseldorf. Since 2004, he is full professor at the Institute of Physical Biology in Düsseldorf and director of the Institute of Complex Systems in the Research Center Jülich.