Prana says study validates efficacy of Alzheimer's drug

By Graeme O'Neill
Friday, 03 February, 2006

Melbourne Alzheimer's disease (AD) drug developer Prana Biotechnology (ASX:PBT, Nasdaq:PRAN) now has visual confirmation of its prototype plaque-buster, clioquinol, at work in an animal brain.

Researchers injected clioquinol radio-labelled with an iodine isotope into a transgenic 'knock-in' mouse model of Alzheimer's disease. Post-mortem radiograms of brain-tissue slices from the mice confirmed the drug had successfully crossed the blood-brain barrier and concentrated in the neocortex, the outer 'thinking' layer of the forebrain.

Prana's metal-protein attenuating compounds (MPACs) have been shown to dissolve amyloid plaques -- aggregations of beta-amyloid fragments excised from APP, by removing copper and zinc ions that hold them together. The metal ions in amyloid plaques spawn oxidising hydroxyl radicals that eventually result in massive loss of neurons from the neocortex and hippocampus, eroding higher cognitive functions and memory.

The Australian-American collaborative study, led by Dr Carlos Opaz of the Oxidation Disorders Laboratory of Victoria's Mental Health Research Institute (MHRI), published its findings in the new journal Aging Cell this week.

The findings lend further support to the once controversial theory of Prana co-founder Professor Ashley Bush, of MHRI Harvard Medical School, that copper and zinc ions are key players in the aetiology of Alzheimer's disease.

"This is the first demonstration in a living animal that clioquinol can be tracked to the biochemical target we have long believed it was attacking, the metal-bound beta-amyloid," Bush said.

He said that, until the new findings, in vivo proof of the specific target of MPACs had been difficult to establish, and the erroneous view that MPACs were merely metal chelators had persisted.

"What is exciting is seeing the injected labelled clioquinol make its way to the area of interest in the brain, and target the zinc-bound plaque-like aggregates in mouse brains," he said. "This visualisation of the MPAC theory in action is really satisfying."

Commercial implications

The observations have commercial implications. According to Diane Angus, Prana's VP for business development, IP and research, the experiment demonstrates the possibility of using radio-labelled MPACs for differential diagnosis of AD, to track the course of the disease, and to assess the efficacy of new-generation drugs in living human brains.

She said Alzheimer's disease accounts for about 50 per cent of all dementia after age 55, and because the living brain is not accessible for tissue sampling, doctors cannot be sure whether they are treating AD, mild cognitive impairment after head trauma, or one of the "slew of terrible dementias" such stroke-associated dementia, vascular dementia.

For most forms of dementia, including AD, a positive diagnosis can only be made after death.

Angus said researchers at the Austin Hospital, who were involved in the study, had been performing exploratory research, using magnetic resonance imaging (MRA) of the living brain to map the distribution of radio-labelled clioquinol associated with amyloid plaques.

She said Prana is considering similar research with its second-generation lead compound, PBT002, but this would require a different radioisotope because of differences in the drugs' chemistry.

With the advent of mechanistic AD drugs like PBT002, which treat the cause of the disease, not just its symptoms, the use of radio-labelled imaging compounds could provide a rapid, direct assessment of how a new therapy was performing, as opposed to current, cognitive readouts, which take many months.

"We can then correlate the images with the cognitive data," she said. "It's still early days, but if we can marry a diagnostic and a therapeutic in the one drug, it will be very powerful."

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