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Cambridge Team Uses SELDI to Suggest Alpha-Defensins as a Risk for Schizophrenia

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Using the SELDI platform, a team led by researchers from the University of Cambridge has identified protein biomarkers they say may be implicated as a risk for developing schizophrenia.
 
The biomarkers, alpha-defensins, have never before been associated with schizophrenia or other forms of psychiatric disorders, Sabine Bahn, the lead author of an article describing the team’s research, told ProteoMonitor this week. And while the biomarkers fall short of being a smoking gun for the disease, she and her colleagues said that they hope the markes will eventually serve to help clinicians diagnose, treat, and even prevent the illness.
 
According to Bahn and her co-authors, approximately 1 percent of the general population is affected by schizophrenia. While symptoms include social withdrawal, delusion, and hallucinations, diagnosis of the disorder is notoriously difficult and often made late in its progression.
 
In addition to providing a means for early-stage diagnosis and treatment for schizophrenia, a biomarker could be the means for a better understanding of the pathology and progression of the disease, Bahn said.
 
Currently, no cure for schizophrenia exists, and the success rate for treating it is only about 30 to 40 percent, she said. But if the disease can be caught early, there may be ways to prevent schizophrenic episodes from occurring that, in turn, lead to more episodes and disease progression.
 
Schizophrenia usually manifests during late puberty to early adolescence, and “If you could identify a person at risk and we could modify their environment during this high-risk, or critical period, it may be possible to prevent the manifestation of the disease,” Bahn said, “because once the brain is matured entirely, which is [during] this period … people are probably less likely to break down with a psychotic episode, which may turn out to become a schizophrenic illness.” 
 
Alpha-defensins are a family of cationic peptides with antibacterial, antiviral, and immunomodulatory capabilities “that represent a major arm of innate immunity,” the authors write in the article, published in the July edition of Molecular & Cellular Proteomics. While the alpha-defensins identified in the study are the first immune-associated protein biomarkers to be implicated in schizophrenia, the immune system has long been suspected to play a role in the disorder.
 
“In schizophrenia, infectious etiology is a strong hypothesis — that perinatal viral infections or parasitic infections may increase the chance of an individual developing schizophrenia,” Bahn said, adding that a massive rise in schizophrenia immediately following the influenza epidemic of the 1920s lends strong support to the theory. “Abnormalities in the immune system of [schizophrenics] have been reported for a long time.”
 
She and her colleagues said in the article that “it is difficult to speculate about the reason for increased alpha-defensins in schizophrenia,” but added that their findings suggest that alpha-defensins may be a predictor of schizophrenia, rather than a biological byproduct of the disease.
 
Proof of Biological Risk?
 
In their work, the researchers used serum samples from 21 pairs of identical twins: one twin from each pair had been diagnosed with schizophrenia, and one twin hadn’t. For its control, the team chose 16 pairs of identical twins where neither twin was diagnosed for the illness.
 
T-cells from both sets of twins were isolated and stimulated and the protein/peptide profiles of CD3+ T-cell lysates from 15 patients with schizophrenia and 15 healthy controls were analyzed. 
 

“If you could identify a person at risk and we could modify their environment during this high-risk, or critical period, it may be possible to prevent the manifestation of the disease.”

Following analysis on the SELDI platform, the research team determined that alpha-defensins were expressed in increased levels in the T-cell lysates of their sample set of schizophrenia patients. Using ELISAs, they confirmed their findings.
 
Next, they turned their attention to plasma. Samples from 21 pairs of identical twins, one twin with schizophrenia, one without, and eight pairs of healthy identical twins were analyzed. Using ELISAs they found that alpha-defensins levels of schizophrenic twins were “significantly higher” than that of healthy twins.
 
Alpha-defensins levels of the healthy twins whose siblings had schizophrenia were also “significantly higher” than that of healthy controls and “at a level intermediate to schizophrenic twins and controls. This was particularly notable because the unaffected discordant twins did not display overt clinical symptoms of schizophrenia but share susceptibility genes as well as risk-associated environmental factors with their affected co-twins,” the authors wrote.
 
Their work so far has not measured the sensitivity or specificity of their biomarker, and Bahn said that by itself, the biomarkers are probably not “very likely to define a complex disease like schizophrenia.”
 
In work following up on the Molecular & Cellular Proteomics article, the authors are using label-free, tandem mass spectrometry to identify additional candidate biomarkers, which they could not see with the SELDI.
 
“We use every technology that is high-throughput and sensitive,” Bahn said. “We are doing different separation techniques, as well, and then we use affinity chromatography to look at glycoproteins, for example … so we’re coupling a number of purification steps.”
 
Using that approach, they’ve identified new biomarkers, many of them associated with immune functions, and changes in glycoproteins, Bahn said.
 
Psynova Neurotech, a company co-founded by Bahn, is developing a predictive test for schizophrenia. The company, founded in 2005 and based in Cambridge, UK, is partnering with Austin, Texas firm, Rules-Based Medicine to co-develop a panel based on about 50 biomarkers that Bahn and her associates have identified as being associated with the disease.
 
RBM, a biomarker-testing laboratory, will use its assays and technology platform to validate the biomarkers. Together, Psynova and RBM also plan to commercialize any test developed. Bahn put an 18-month timetable for development of a biomarker panel and an initial homebrew test, and a three-year timetable for a fully commercialized and reimbursable test.
 
Bahn and her collaborators have also been in contact with the US Army and may be receiving blood samples from officers who were diagnosed with schizophrenia after enlistment. In some cases, samples go back as far as 10 years before diagnosis, which would allow them to do a better profile of pre-schizophrenia patients.
 
In addition to searching for biomarkers that may predict schizophrenia, Bahn and her collaborators also are analyzing blood samples taken from patients with prodromal schizophrenia — in which a person may show some signs of the disease but hasn’t developed full-blown schizophrenia — to find differences in protein expression compared to patients with the disease and healthy controls to better understand the pathology of schizophrenia.
 
Because schizophrenia is an umbrella diagnosis for an ailment with different manifestations and different responses to a various therapies, successful treatment has been elusive, Bahn said. She and her colleagues are researching the response of patients diagnosed with the disease to different drug treatments.
 

“If we can partner with big pharma, and sub-stratify patients according to their biomarker signature, we may find that some drugs are very, very effective in a sub-group of patients, and that may result in personalized medicine, obviously, but [also in] a better understanding of the pathological processes … then you can do deeper analysis. At the moment everything is lumped together, and that is why we’re not moving forward,” Bahn said.

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