Prana surges on study validating its metal-ion theory

Shares in Melbourne drug-discovery company Prana Biotechnology (ASX:PBT, NASDAQ:PRAN) have surged by some 30 per cent after the Journal of Neuroscience published a new study last week that further validates the metal-ion theory of Alzheimer’s developed by Prana founder and Dr Ashley Bush.

Prana also appears to have been a beneficiary of an article in leading US business newspaper The Wall Street Journal in which a young Alzheimer’s investigator at Harvard Medical School, Dr Jie Shen, described the obstacles she and her team had encountered publishing a study that challenged the long-dominant “amyloid hypothesis” of Alzheimer’s disease.

Last week’s WSJ article followed the publication of an interview in the paper late last year in which Bush described his own experiences in attempting to convince the Alzheimer’s research community of the merits of his controversial hypothesis, which proposes that the real culprits in the disease are copper and zinc ions that cause a protein fragment, beta-amyloid, to aggregate in brain tissues, and which spawn reactive hydroxyl radicals that intoxicate and eventually kill neurons.

Prana also appears to have come to the notice of international investors after the prestigious Forbes business magazine placed the company’s experimental metal-chelating drugs for Alzheimer’s disease on its watch-list of promising neurological drugs.

And Prana CEO Dr Geoff Kempler believes another factor in the company’s improving fortune was its appointment of Wall Street biotech guru Dr John Alsenas to its board. Alsenas has been a consultant to a number of small, successful biotechnology companies with promising new therapeutics, and has a track record for picking winners in the sector.

The paper published in this month’s issue of the Journal of Neuroscience describes how a team led by Dr Avi Friedlich, in Bush’s Laboratory for Oxidation Biology at Harvard Medical School, knocked out the gene for a zinc-transport protein called ZnT3, in a transgenic mouse.

Neurons in the neocortex – the region of the brain devoted to memory and higher cognitive function – store the ZnT3 protein in the synaptic vesicles of neurons. It mediates a buildup of zinc (Zn++) ions that flow out of the vesicles whenever the nerve “fires”.

Bush’s team was exploring the possible role of the ZnT3 Protein in cerebral amyloid angiopathy (CAA)- a buildup of amyloid plaque in the blood vessels of the neocortex, commonly observed in the post-mortem brains of Alzheimer’s patients.

They found that, in normal mice, ZnT3-mediated zinc transport creates an exchangeable pool of zinc ions in the walls of blood vessels. In a transgenic mouse model of human Alzheimer’s disease, the pool of zinc ions is enriched in comparison to normal mice.

Not only is the pool of zinc ions reduced in blood vessel walls in new ZnT3-knockout mouse, there is a dramatic reduction in the buildup of amyloid plaques within the blood vessels of the neocortex, as well as within the bloodstream itself.

The team speculates that the buildup of amyloid in cerebral blood vessels may exacerbate the mental confusion of Alzheimer’s disease by restricting the flow of oxygen to oxygen-hungry neurons.

If this is so, zinc-chelating drugs like Prana’s experimental compounds PBT-1 (the old antibiotic clioquinol) and its new synthetic copper-zinc chelator PBT-2, may reduce the symptoms of Alzheimers by limiting the buildup of zinc ions in blood vessels in the brain.

Prana’s research has already shown that clioquinol’s copper- and zinc-chelating activity can dissolve insoluble amyloid plaques in vitro by removing the metal ions that bind the beta-amyloid fragments together.

And Prana’s experiments with a mouse model of a virulent variant of human Alzheimer’s disease has shown that PBT-1 dramatically reduced the cognitive “haze” and memory impairment associated with the disease – the new Neuroscience paper offers a potential explanation for this effect, in terms of plaque clearance from blood vessels, and improved blood flow to oxygen-deprived neurons.