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Proteome Sciences to Commercialize Two Protein Biomarker Assays for Alzheimer's Disease

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This story originally ran on July 14.

By Adam Bonislawski

Proteome Sciences announced this week that it has developed two multiplex protein biomarker assays for Alzheimer's disease in collaboration with scientists at the Institute of Psychiatry, King's College, London, that it plans to commercialize by the fall.

The assays use multiple-reaction-monitoring mass spectrometry to measure the level of proteins associated with Alzheimer's disease and could be useful as diagnostic tests or research tools for pharmaceutical companies developing drugs targeting the disease, Ian Pike, Proteome Sciences' chief operating officer, told ProteoMonitor.

One of the assays employs a panel of nine plasma proteins – including known Alzheimer's biomarkers like ApoE and clusterin and new markers like gelsolin, alpha-2-macroglobulin, and complement factor H – that Pike said have potential to aid in early detection or prognosis of Alzheimer's.

Some of the nine proteins "we think are very helpful in early detection of the disease in the prodromal phase and others are going to be useful in predicting how the disease is going to progress," he said. "We've developed SRM assays for all nine proteins. So we use somewhere between one and three peptides per protein and three transitions per peptide to allow us to develop a quantitative assay."

So far, the company has tested around 100 samples with the mass spec assay. In addition, "some of the markers have been screened by the [Institute of Psychiatry] using Western blots or other immunoassay approaches in several hundred patients. So we're comfortable that these are relevant," Pike said.

Key to the assay is that it uses plasma instead of cerebrospinal fluid – the matrix in which Alzheimer's biomarker work has most commonly been done. Plasma-based tests are more desirable because of the greater accessibility of plasma samples compared to CSF, but researchers have had trouble detecting Alzheimer's biomarkers in plasma because the blood-brain barrier prevents many of these proteins from entering the bloodstream.

"There have been some proteomic analyses in plasma before, but the results haven't always been replicable," Neil Buckholtz, chief of dementias of aging at the National Institute on Aging, told ProteoMonitor last month regarding another effort – this one by Rules-Based Medicine and the Alzheimer's Disease Neuroimaging Initiative – to detect protein biomarker signatures in blood (PM 06/11/2010).

"It's clear that there is a [biomarker] signature of some use in CSF, and it's certainly the best clinically available method at the moment, but realistically when you're looking at global populations in the tens of millions, this is not going to be a readily implementable testing matrix," Pike said. "If we can get blood tests working, that will be much more effective and economically viable as a way of early detection and monitoring of the disease."

The second assay uses mass spectrometry to investigate phosphorylation levels of tau protein in brain tissue, which is associated with Alzheimer's disease. This assay could be useful for pharmaceutical companies interested in monitoring tau phosphorylation levels to determine the effectiveness of various therapies in preclinical testing, Pike said. The use of mass spec will enable researchers to look at phosphorylation sites that have previously gone unexamined, he added.

"Generating antibodies against phosphorylation sites is really quite challenging, and for some of them they're so close together that discriminating the sites by immunological methods is probably impossible," he said. "We've developed an assay for four key [phosphorylation] sites in murine and human tau protein, and we're looking to expand the number of sites that we cover. There are multiple sites that haven't been reported on."

Last month Surrey, UK-based Proteome Sciences announced a proposed placing and open offer to raise up to £6.9 million ($9.9 million). The money was intended, in part, to fund commercialization of the new Alzheimer's assays, Pike said. The company recently acquired a Thermo Fisher TSQ Vantage triple quadrupole machine for its ISO 9001-accredited facility in Frankfurt, Germany, out of which it plans to offer the assays beginning in August.

"We'll offer them on a straight price-per-sample basis. People will send in their samples and we'll run the assays and report back," Pike said.

The company is also involved in discussions with several in vitro diagnostics manufacturers about licensing some of the biomarkers for the development of an IVD test.

In the meantime, Pike said, trials will continue to further verify the Alzheimer's biomarker panel.

"We're engaging with the Institute of Psychiatry. We jointly hold a research grant from the [UK]s] Medical Research Council to develop these biomarkers, and through that we have access to very large clinical cohorts," he said. "We're in the process of using our mass spectrometry-based tests to go through large numbers of samples. That's a process that will clearly take a period of time to complete."

Last July, Proteome Sciences announced a collaboration with Millipore to develop multiplex immunoassays on the Luminex platform to measure Alzheimer's biomarkers for researching the disease (GWDN 06/07/2009). Under the agreement, Proteome Sciences retained all rights to clinical applications of these biomarkers, some of which, Pike said, are also part of the nine-marker panel just announced.

The company presented its new mass spec-based assays this week in Honolulu at the 2010 International Conference on Alzheimer's Disease. Earlier this month, a team of researchers, including some of the company's collaborators at the Institute of Psychiatry, published a study in Archives of General Psychiatry on plasma-based Alzheimer's biomarkers that tied increased plasma concentrations of the protein clusterin to increases in the brain of the amyloid-beta fibrils characteristic of the disease.

"[The paper] is impressive for its depth and breadth," John Trojanowski, a researcher at the University of Pennsylvania School of Medicine and a director of the ADNI Biomarker Core, told ProteoMonitor via e-mail. "It will be important to study larger numbers of AD and control subjects, and especially those with non-AD dementia to confirm and extend these studies."

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