Promising drug halts a metal-mediated chemical reaction in the brain
Trapping metals could prove a key to curing Alzheimer’s disease, according to the promising results of early clinical trials on a compound called PBT2. The potential drug, owned by Australian biotechnology company Prana, interrupts a metal-mediated chemical reaction that causes amyloid beta, a 42 amino acid peptide, to aggregate in plaques in the brain of Alzheimer’s patients.
In a placebo-controlled trial in subjects with early Alzheimer’s, published in Lancet Neurology, those given 250mg of PBT2 once a day performed significantly better in two cognitive function tests after just 12 weeks. The levels of amyloid beta in their spinal fluid were also lower.
’The drug targets a reaction between amyloid beta and the ionic zinc and copper that are released into the glutamate synapses [junctions between neurons] affected by Alzheimer’s,’ explains Ashley Bush of the Mental Health Research Institute of Victoria in Australia, one of the authors of the clinical study of PBT2. ’When the amyloid beta reacts with copper ions, it aggregates into clumps and becomes redox permissive, generating radical chemistry and reactive oxygen species.’
Prana is an academic spin-out company launched by some of the researchers developing PBT2 - which is now the company’s lead Alzheimer’s drug - to commercialise research into Alzheimer’s disease and age-related neurodegenerative disorders.
Craig Ritchie of Imperial College London in the UK, a specialist in old age psychiatry, is Prana’s chief European clinical advisor. He believes that this aggregation of monomeric amyloid beta is only possible in the presence of the ions that the drug traps. ’There are binding sites for those metals on the monomeric amyloid beta, which form dityrosine bonds and become less soluble when they are aggregated,’ he explains. These insoluble aggregates remain in the brain and appear to play a critical role in the formation of the distinctive Alzheimer’s plaques.
Bush, Ritchie and colleagues have been working on the idea since the early 1990s. ’At first, we thought metal chelators could be of some use,’ says Bush. ’But these also perturb a lot of essential metal ion chemistry, and they don’t pass across the blood-brain barrier very well. So the chemistry challenge was to find a less strong chelator.’
They took advantage of the fact that the normal metal binding site that develops in amyloid beta accumulations in the brain is hydrophobic, but it traps metals. So they looked for ionophoric molecules - lipid-soluble molecules that form complexes with ions and transport them across cell membranes - that selectively target the metals in this hydrophobic binding site.
Initial trials on an old antifungal, clioquinol, were promising. ’PBT2 is a great improvement,’ Bush claims. ’It has the same 8-hydroxyquinoline scaffold, but we removed some elements we didn’t like, such as an unstable iodine atom that was also a problem for large-scale manufacture. PBT2 has no iodine, its synthesis is simple and, importantly, it is much more enriched in the brain.’
The team is now working on the design of a large-scale trial, and Ritchie is optimistic. ’Ever since the early 1990s, the idea was to create a drug that doctors could prescribe, and nothing I’ve seen has put me off that track,’ he says. ’Hopefully five years down the line we will be seeking a licence for PBT2.’
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L Lannfelt et al, Lancet Neurology, 2008, DOI: 10.1016/S1474-4422(08)70167-4