Biomarkers And MicroRNA

Ezose Sciences Inc. today announced an alliance with Fast Forward, LLC, a subsidiary of the National Multiple Sclerosis Society, to use Ezose’s GlycanMap® technology in the discovery of biomarkers to help diagnose multiple sclerosis (MS) and improve disease management.

GlycanMap® technology enables the study of glycomics via automated analysis of the sugar molecules known as glycans that attach to proteins in the body and affect their biochemical function. The speed and high-throughput of this technology hold the potential to discover new biomarkers and targets that can improve the diagnosis and management of disease and enhance the efficiency of development of new therapeutic options.

To execute the research program, Ezose will collaborate with Anthony Reder, M.D., Professor of Neurology at the University of Chicago Medicine and a recognized expert in the clinical and laboratory research of multiple sclerosis. The research goal is to discover new biomarkers associated with MS, enabling earlier, surer diagnosis of the disease, distinguishing it from other neurological disorders, and to identify sub-types of MS. These biomarkers would then be incorporated in diagnostic tests to improve prognosis, aid in therapy selection, and evaluate response to therapy. They would also be useful in guiding the development of new therapies by increasing R&D speed and efficiency.

Under the terms of a sponsored research agreement, Ezose will receive up to $390,000 from Fast Forward to support the project.

“In its support of biotechnology companies, Fast Forward is establishing a model to combine the innovation of researchers in industry with the insights of leading physician-scientists at academic medical centers,” said Scott A. Siegel, Ph.D., Chief Operating Officer of Ezose. “We at Ezose are eager to start work with Professor Reder to leverage the potential of our unique glycomics technology and serve people living with multiple sclerosis.”

“This alliance with Ezose is another example of Fast Forward’s commitment to identifying promising technology and novel treatment approaches to bridge the gap between research discoveries and product development that will speed efforts to stop MS, restore function and end the disease forever,” said Timothy Coetzee, Ph.D., Chief Research Officer of the National MS Society.

About Glycomics

Glycomics is the study of glycans, the sugar chains that during the biochemical process known as glycosylation become attached to many proteins expressed by human cells. The particular glycans involved may crucially determine the function of the resulting glycoprotein and its role in health and disease.

Glycomics is a natural complement to genomics and proteomics, but it has traditionally been hindered by the lack of practical high-throughput and quantitative technologies. Ezose’s proprietary GlycanMap® platform addresses this need by combining, in an automated 96-well format, high-throughput glycan enrichment with specialized MALDI-TOF mass spectrometry and custom bioinformatics to both structurally identify and quantitate glycans present in complex biological samples. Such glycans can serve as novel biomarkers to aid in the development of drugs, vaccines, and diagnostic tests, including companion diagnostics. In addition, glycomics holds potential for uncovering new therapeutic targets and mechanisms and for guiding the development and manufacture of glycosylated biologics and biosimilars.

About Ezose

Ezose (pronounced a-zose) Sciences Inc., based in Pine Brook, NJ, is dedicated to advancing glycomics to improve scientific understanding and healthcare. Ezose’s proprietary GlycanMap® technology platform brings a new dimension to biomarker discovery by enabling glycomics research on a scale comparable to that of genomics and proteomics. Ezose offers glycomics capabilities ranging from glycan analytics and biomarker discovery to diagnostic development and commercialization. The company tailors these capabilities to the needs of corporate partners under collaborative R&D and analytical-services agreements.

Established in 2009 as a US company, Ezose is an affiliate of the Diagnostics Division of Shionogi & Co., Ltd., Osaka, Japan.

About Fast Forward, LLC

Fast Forward, LLC is a nonprofit organization established by the National Multiple Sclerosis Society in order to accelerate the development of treatments for MS. Fast Forward accomplishes its mission by connecting university-based MS research with private-sector drug development and by funding small biotechnology/pharmaceutical companies to develop innovative new MS therapies and repurpose FDA-approved drugs as new treatments for MS.

Source: Herald Online Copywrite Rock Hill Herald Online (24/10/12)

A buildup of sodium in the brain detected by magnetic resonance imaging (MRI) may be a biomarker for the degeneration of nerve cells that occurs in patients with multiple sclerosis (MS), according to a new study published online in the journal Radiology.

The study found that patients with early-stage MS showed sodium accumulation in specific brain regions, while patients with more advanced disease showed sodium accumulation throughout the whole brain.

Sodium buildup in motor areas of the brain correlated directly to the degree of disability seen in the advanced-stage patients.

"A major challenge with multiple sclerosis is providing patients with a prognosis of disease progression," said Patrick Cozzone, Ph.D., director emeritus of the Center for Magnetic Resonance in Biology and Medicine, a joint unit of National Center for Scientific Research (CNRS) and Aix-Marseille University in Marseille, France.

"It's very hard to predict the course of the disease."

In MS, the body's immune system attacks the protective sheath (called myelin) that covers nerve cells, or neurons, in the brain and spinal cord. The scarring affects the neurons' ability to conduct signals, causing neurological and physical disability.

The type and severity of MS symptoms, as well as the progression of the disease, vary from one patient to another.

Dr. Cozzone, along with Wafaa Zaaraoui, Ph.D., research officer at CNRS, Jean-Philippe Ranjeva, Ph.D., professor in neuroscience at Aix-Marseille University and a European team of interdisciplinary researchers used 3 Tesla (3T) sodium MRI to study relapsing-remitting multiple sclerosis (RRMS), the most common form of the disease in which clearly defined attacks of worsening neurologic function are followed by periods of recovery.

Sodium MRI produces images and information on the sodium content of cells in the body.

"We collaborated for two years with chemists and physicists to develop techniques to perform 3T sodium MRI on patients," Dr. Zaaraoui said.

"To better understand this disease, we need to probe new molecules. The time has come for probing brain sodium concentrations."

Using specially developed hardware and software, the researchers conducted sodium MRI on 26 MS patients, including 14 with early-stage RRMS (less than five years in duration) and 12 with advanced disease (longer than five years), and 15 age- and sex-matched control participants.

In the early-stage RRMS patients, sodium MRI revealed abnormally high concentrations of sodium in specific brain regions, including the brainstem, cerebellum and temporal pole. In the advanced-stage RRMS patients, abnormally high sodium accumulation was widespread throughout the whole brain, including normal appearing brain tissue.

"In RRMS patients, the amount of sodium accumulation in gray matter associated with the motor system was directly correlated to the degree of patient disability," Dr. Zaaraoui said.

Current treatments for MS are only able to slow the progress of the disease. The use of sodium accumulation as a biomarker of neuron degeneration may assist pharmaceutical companies in developing and assessing potential treatments.

"Brain sodium MR imaging can help us to better understand the disease and to monitor the occurrence of neuronal injury in MS patients and possibly in patients with other brain disorders," Dr. Ranjeva said.

More information: "Distribution of Brain Sodium Accumulation Correlates with Disability in Multiple Sclerosis–A Cross-Sectional 23Na MR Imaging Study." Radiology.

Source: Medical Xpress © Medical Xpress 2011-2012 (18/07/12)

Biogen Idec Inc. said that it will work with Regulus Therapeutics Inc. to identify microRNAs biomarkers in patients with multiple sclerosis.

Biogen makes and sells several multiple sclerosis drugs including Avonex and Tysabri, and it is also developing BG-12, a pill that is seen as a promising treatment for the condition. The companies said Regulus believes the biomarkers may help identify the best patients for clinical trials of multiple sclerosis drugs, could be used to develop diagnostic tests and may help monitor the progression of the illness or relapses.

MicroRNAs are small RNA molecules. RNA helps synthesize proteins in the body, and microRNA helps regulate the way genes work.

Biogen will buy a stake in Regulus and will make upfront and potential milestone payments to the company. It did not disclose the size of the stake it is buying or the terms of any payments.

Multiple sclerosis is a disease in which the immune system attacks healthy nerves. It can cause pain, numbness, slurred speech, impaired vision, muscle weakness, and neurological problems.

Source: Bloomberg @2012 BLOOMBERG L.P (16/08/12)

NextGen Group plc announced that its US-subsidiary NextGen Sciences Inc, a leader in biomarker discovery, measurement and qualification, has launched its csfmultiplesclerosis25 multiplex protein assay for multiple sclerosis. The assay simultaneously measures 25 human CSF (cerebrospinal fluid) proteins that are believed to have potential as biomarkers for the disease.

Klaus Rosenau, Chairman and CEO of NextGen Group, commented, ‘The release of the csfmultiplesclerosis25 assay is another piece in our strategy of developing assays with protein content that is relevant to the CNS market we are striving to address. To ensure we continually deliver the high-quality assays that pharmaceutical, biotechnology and diagnostics companies need to inform their decision-making processes, NextGen Sciences is currently working to expand its CSF and Plasma discovery assays.’

NextGen’s assay is based upon its multiple reaction monitoring (MRM) mass spectrometry platform and generates high quality reproducible data that companies can use in their drug and diagnostic development programmes. The MRM platform can be used to assay proteins and modified proteins for which there are no antibodies and can thus circumvent the limitations of current antibody based technologies.

NextGen expects to develop further oncology and CNS disease-focused assay panels, both as proprietary products and with other companies, through partnerships and collaborations.

Source: PR Web (28/07/11)

Several short, noncoding RNA molecules are associated with multiple sclerosis symptoms, perhaps in enough of a causal way to become therapeutic targets as well as biomarkers of disease, a researcher said here.

These so-called micro RNA species, or miRNAs, may be critical in shifting immune responsiveness away from the benign Th2 profile, instead promoting pro-inflammatory Th1/Th17 responses, said Mireia Guerau de Arellano, PharmD, PhD, of Ohio State University in Columbus.

Moreover, she told attendees at the annual meeting of the Consortium of Multiple Sclerosis Centers (CMSC) that their relative levels differ in relapsing-remitting and secondary progressive MS versus primary progressive disease, which otherwise have been difficult to distinguish biologically.

Originally dismissed as "junk" in the human genome, miRNAs have since been found to be key regulators of gene expression, Guerau explained. In particular, they can silence protein-coding genes by inhibiting their translation or inducing destruction of messenger RNA molecules.

Her research group went looking for miRNAs that were differentially expressed in CD4-positive T cells taken from 22 MS patients compared with 12 healthy controls.

The patients included 12 with relapsing-remitting MS and five each with secondary or primary progressive disease.

Most promising as biomarkers were miRNA species designated as miR-128, miR-340, and miR-27a-b.

They all appear to control expression of a gene known as BMI-1. It has no relation to body mass index -- rather, it has previously been found to play a role in cellular housekeeping, as part of the ubiquitin-proteasome pathway.

Previous research has indicated that BMI-1 is involved in some way with immune function, in that its deficiency impairs Th2 functioning and promotes Th1 responses, Guerau said.

Oncology studies have also found that miR-128 actively represses BMI-1 function. So do miR-340 and miR-27a-b, she said.

Expression of these latter miRNAs was significantly increased in the MS patients in her study relative to controls (P<0.05).

Moreover, miR-340 in particular was significantly increased in the five patients with primary progressive MS relative to the controls (P=0.03).

Transfecting the three miRNA species into mice made them more susceptible to experimental autoimmune encephalitis (EAE), the standard rodent model of MS, Guerau said.

EAE severity scores were tripled in the miRNA-expressing mice compared with control animals.

The potential for targeting these miRNAs with drugs was suggested by in vitro experiments, Guerau added. Treating naive CD4-positive T-cells from MS patients with specific inhibitors of these miRNAs partially restored a more Th2-like pattern of cytokine release, she said.

Cells from the patients treated with the inhibitors showed about a 150% increase in interleukin-5 production, which is indicative of a Th2 response.

"This shows potential for a therapeutic strategy, though there are still a lot more experiments needed in that regard," she said.

The study was funded by the National Institute of Neurological Diseases and Stroke.

Guerau and other researchers on the study declared they had no relevant financial interests.

Source: MedPage Today © 2011 Everyday Health, Inc (06/06/11)

Biomarkers – mainly defined as surrogates serving as indicators for specific biological states – play an ever-increasing role in neuroscience and especially in the management of multiple sclerosis, scientists reported today at the 21st Meeting of the European Neurological Society (ENS) in Lisbon.

In analyzing gene expression patterns, immunological changes and imaging abnormalities, physicians are now able to detect complex nervous diseases at an early stage, to better discern them from other types with similar clinical manifestations, to better foresee the outcome and to evaluate whether or not a patient responds adequately to a specific therapy.

Biomarkers – surrogates which can be objectively measured and used as indicators for certain biological states, salutogenetic or pathogenetic processes or responses to pharmacological treatments – are of increasing importance in many areas of modern medicine, but especially so in neuroscience. Neurological diseases are most complex in nature, sometimes difficult to detect, and when relying only on clinical examinations, the effect or ineffectiveness of a therapy might become evident at a late stage.

“Especially in multiple sclerosis (MS) and some related disorders such as optic neuritis and neuromyelitis optica, a number of new biomarkers now greatly help us to quickly and non-invasively confirm or reject a diagnosis, to anticipate the outcome and to check whether or not the chosen therapy is effective in this particular patient,” Prof. Massimo Filippi said today at the 21st Meeting of the European Neurological Society (ENS) in Lisbon. More than 3,200 neurological experts from around the world are currently discussing the latest developments in all areas of their specialty in the Portuguese capital.

Massimo Filippi, Professor of Neurology, heads the Interdepartmental Research Programme “BrainMap” and the Neuroimaging Research Unit at the Scientific Institute and University “Vita-Salute”, Ospedale San Raffaele in Milan, Italy. “These are big steps towards therapies that can be speedily customised to a specific patient’s situation in these most burdensome types of diseases.”

600.000 Europeans suffer from multiple sclerosis
According to epidemiological studies, about 600.000 Europeans and 2.8 million persons worldwide suffer from MS, an inflammatory disease in which the myelin sheaths insulating the axons in the brain and the spinal cord are disintegrated, causing a wide array of clinical manifestations and leading to progressive physical and often cognitive disability. “The huge variability of symptoms, caused by the fact that MS can affect any part of the CNS, along with a lack of meaningful laboratory and paraclinical tests, led in the past to delayed or uncertain diagnoses,” Prof. Filippi added. “We are that much happier, therefore, that in recent years we could trace a remarkable number of biomarkers, allowing for an improved and quickened assessment of the disease and its progression.”

Improved MS diagnosis and differential diagnosis
Optic neuritis, an inflammation of the optic nerve potentially leading to a total loss of vision, can be an early sign for MS. “We now found out that the gene expression patterns in a whole blood analysis show significant differences in patients with optic neuritis compared to healthy controls, which can make an early detection of MS easier in the future,” Prof. Filippi said. Neuromyelitis optica (Devic’s disease) is characterised by inflammatory-demyelination and irreversible tissue loss concentrated in the spinal cord and the optic nerve. Seen by some as a subtype of “ordinary” MS and by others as a different, independent disease, it needs a different course of treatment than MS to achieve optimal results. “Neuromyelitis optica is characterised by an autoantibody profile distinct from that of MS, allowing for an improved differential diagnosis and an early start of the appropriate therapy,” Prof. Filippi added.

Anticipating disease progression
In MS, neurologists discern different phenotypes – including the relapsing-remitting, the primary progressive and the secondary progressive. Each of these has a different prognosis and may require different therapeutic approaches. As a consequence, there is an urgent need to define their pathophysiology. “Some of our new biomarkers make this job much easier,”

Prof. Filippi explains. “For example, in so-called black holes, lesions with irreversible tissue damage, the patterns of the microglia activation are different in progressive MS as compared to the relapsing subtype. MR measures could also help characterizing the heterogeneous clinical phenotypes of the disease. In particular, patients with progressive MS have an over-recruitment of the cervical cord on functional MRI scans, which is more pronounced in secondary progressive than in primary progressive MS. In relapsing-remitting MS patients, diffusion tensor magnetic resonance imaging (DT-MRI) allows distinguishing the effects of specific tract damage on disability and cognitive impairment. Finally, in neuromyelitis optica, the presence of NMO-IgG (antibodies which destroy aquaporin-4, a protein serving as a water channel through the cell membrane) already in an early stage identifies patients with a worse prognosis.”

Evaluating the response to treatment for MS
Does an individual patient respond to treatment? This crucial question, too, can in many cases be answered with hitherto unknown efficacy due to new biomarkers and technology to measure them. “The longitudinal atrophy of the spinal cord, a potentially important indicator for disease evolution and treatment response, can now be evaluated more effortlessly by a new segmentation method,” Prof. Filippi continues. “Whether or not a patient responds to natalizumab, a synthetically created monoclonal antibody designed to block the destructive activity of white blood cells in MS, can be assessed by the amount of natalizumab binding to mononuclear cells found in peripheral blood. A marker for the chances that cladribine -- a drug targeted to inhibit the immune system overactive in MS patients --will actually reduce disease activity is the amount of activity measured before treatment: the more relapses, the more active brain lesions and the more progression in disability, the more effective the drug will probably be. The effectiveness of an immunosuppressive treatment in neuromyelitis optica can in turn be measured by the NMO-IgG (aquaporin-4-antibody) level: the lower it is, the better the response to therapy; the higher it is, the more probable are relapses.”

A new area in MS assessment
“With these discoveries, and many more possible biomarkers still under investigation, we are embarking on nothing less than a new area of CNS disease assessment,” Prof Filippi concludes. “Instead of being in the dark for months and years, or dependent on very expensive and burdening diagnostic tools, we increasingly understand an easier-to-read bio-language of the body. It is leading us on relatively simple paths to the right diagnosis and letting us watch the development of disease and/or treatment. We expect this shift in diagnostic paradigms to continue and to yield even more exciting possibilities within the next few years.”

Source: European Hospital Copyright 1997-2009 by EUROPEAN HOSPITAL Verlags GmbH (31/05/11)

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