Australian researchers identify Alzheimer’s Disease-modifying drug candidate

Australian scientists are reporting marked improvement in Alzheimer’s transgenic mice following treatment with the ionophore PBT2, a finding the scientists believe could lead to the development of the first disease-modifying drug for Alzheimer’s Disease.

Amy Swinderman
VICTORIA, Australia—Australian scientists are reporting marked improvement in Alzheimer's transgenic mice following treatment with the ionophore PBT2, a finding the scientists believe could lead to the development of the first disease-modifying drug for Alzheimer's Disease (AD).

The study, led by researchers from the Mental Health Research Institute of Victoria and the University of Melbourne and published in the July 10 issue of Cell Press' journal Neuron, provides the first demonstration that an ionophore, a compound that transports metal ions across cell membranes, can elicit rapid and pronounced improvement in neuropathology and cognitive function in mouse models of AD.

"This is by far the most potent oral drug candidate I have ever seen tested in these mice," says the study's senior author, Dr. Ashley I. Bush from the Mental Health Research Institute of Victoria. "I hope that the system we have developed for identifying drugs based upon metal reactions will lead to the first disease-modifying drug for AD, which is very much needed."

In 2001, Bush and a team of researchers published findings describing the benefits of clioquinol, a hydrophobic metal binding agent that suppressed Alzheimer pathology in transgenic mice. However, further studies in mice and humans demonstrated that brain entry of CQ was quite limited, and clioquinol was difficult to synthesize for large-scale clinical trials, Bush says.

"The current work represents that animal data on the second generation version, called PBT2," he says. "It was designed by Prana Biotechnology Ltd., to have greater brain penetration and to be more potent than clioquinol."

Given orally to two types of amyloid-bearing transgenic mouse models of AD, PBT2 outperformed CQ by markedly decreasing soluble interstitial brain amyloid beta protein (Aß) within hours and improving cognitive performance to exceed that of normal littermate controls within days. Nontransgenic mice were unaffected by PBT2.

"I was not surprised that drug worked well on mice in alleviating Alzheimer brain pathology," Bush says. "What was surprising was how fast it improved cognitive performance on the maze task. The animals recovered full memory function within days of treatment. These results encourage us to believe that PBT2 might be able to be a disease-modifying drug for Alzheimer's Disease—drugs for AD are currently only symptomatic and do not modify the underlying disease."

On the basis of these results, PBT2 has proceeded to complete toxicology and Phase 1 testing, and has recently completed a Phase IIa clinical trial, Bush says.

"I am not yet allowed to describe the results of the Phase 2a clinical trial, but clearly, this drug needs to go on to large-scale clinical trials," he says. "For my basic research, I am exploring exactly how aging fatigues metal homeostasis systems that lead to the abnormal reaction of amyloid with normal synaptic zinc and copper. I am also looking at the function of amyloid and its precursor. Not surprisingly, I have evidence that they normal participate in metal regulation."

Co-authors of the study included Prana Biotechnology Ltd. and Monash University in Victoria, Australia; Royal Free & University College Medical School in London; and Massachusetts General Hospital in Charlestown, Mass.

Amy Swinderman

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