S2-04-04: Rational therapeutic strategies for modifying Alzheimer's disease: Abeta oligomers as the validated target

Abstract

In 1984 we described the oligomerization of Aβ and some of the biochemical factors which affect its stability. Subsequently, we found that metal ions such as Zn2+ and Cu2+ play a major role in the oligomerization process, and that the soluble oligomeric species of Aβ are the principal determinants of the degree of neurodegeneration. We next identified compounds which were capable of interfering with the metal-induced oligomerization of Aβ. Prana Biotechnology (PBT) was founded to commercialize these discoveries, and the first compound (clioquinol – CQ) was shown to have favorable preclinical properties and some efficacy in an early Phase 2 clinical trial. Further medicinal chemistry on the 8-OH quinoline scaffold yielded a much-improved compound, PBT2, with high brain penetrability. CQ and PBT2 are efficient at inhibiting Zn2+ and Cu2+-induced Aβ oligomerization and Cu2+-induced dityrosine formation. In transgenic mouse AD models, CQ and PBT2 effectively: lower soluble oligomer and insoluble Aβ levels in brain interstitial fluid dialysate and Aβ plaque levels; reverse Aβ-induced inhibition of LTP in hippocampal slices; improve the behavioral phenotype in the Morris Water Maze; lower tau, and increase synaptophysin levels. PBT2 has now been taken through early clinical development. In a recently completed Phase 2 study, the compound was found to be safe at 50 and 250mg per day for 12 weeks. CSF Aβ42 was significantly reduced at the higher dose, with a significant dose-effect. Two tests of cognitive executive function also showed significant improvements at the higher dose. Aβ-amyloid neuroimaging using PET offer the tools for monitoring the efficacy of Aβ-directed drug interventions, and shows a highly significant correlation of Aβ-amyloid burden with cognitive impairment during the evolution of the preclinical phases of AD. Collectively, these data provide evidence that orally bioavailable drugs designed to inhibit toxic oligomeric species of Aβ in human subjects with Alzheimer's disease have the potential to modify the course of the illness.