Biomarkers and microRNA
For some, the disease multiple sclerosis (MS) attacks its victims slowly and progressively over a period of many years. For others, it strikes without warning in fits and starts. But all patients share one thing in common: the disease had long been present in their nervous systems, hiding under the radar from even the most sophisticated detection methods. But now, scientists at the Gladstone Institutes have devised a new molecular sensor that can detect MS at its earliest stages -- even before the onset of physical signs.
In a new study from the laboratory of Gladstone Investigator Katerina Akassoglou, PhD, scientists reveal in animal models that the heightened activity of a protein called thrombin in the brain could serve as an early indicator of MS. By developing a fluorescently labeled probe specifically designed to track thrombin, the team found that active thrombin could be detected at the earliest phases of MS -- and that this active thrombin correlates with disease severity. These findings, reported online in Annals of Neurology, could spur the development of a much-needed early-detection method for this devastating disease.
MS, which afflicts millions of people worldwide, develops when the body's immune system attacks the protective myelin sheath that surrounds nerve cells. This attack damages the nerve cells, leading to a host of symptoms that include numbness, fatigue, difficulty walking, paralysis and loss of vision. While some drugs can delay these symptoms, they do not treat the disease's underlying causes -- causes that researchers are only just beginning to understand.
Last year, Dr. Akassoglou and her team found that a key step in the progression of MS is the disruption of the blood brain barrier (BBB). This barrier physically separates the brain from the blood circulation and if it breaks down, a blood protein called fibrinogen seeps into the brain. When this happens, thrombin responds by converting fibrinogen into fibrin -- a protein that should normally not be present in the brain. As fibrin builds up in the brain, it triggers an immune response that leads to the degradation of the nerve cells' myelin sheath, over time contributing to the progression of MS.
"We already knew that the buildup of fibrin appears early in the development of MS -- both in animal models and in human patients, so we wondered whether thrombin activity could in turn serve as an early marker of disease." said Dr. Akassoglou, who directs the Gladstone Center for In Vivo Imaging Research (CIVIR). She is also a professor of neurology at the University of California, San Francisco, with which Gladstone is affiliated. "In fact, we were able to detect thrombin activity even in our animal models -- before they exhibited any of the disease's neurological signs."
In laboratory experiments on mice modified to mimic the signs of MS, the team employed an Activatable Cell-Penetrating Peptide (ACPP), a special type of molecular probe that delivers fluorescent agents to a region of interest. For this study, they developed a thrombin-specific ACPP that could track thrombin activity in mice as the disease progressed. They then carefully analyzed where -- and at what stage of disease -- thrombin activity was found.
"We detected heightened thrombin activity at specific disease 'hot-spots,' regions where neuronal damage developed over time," said Gladstone Staff Research Scientist Dimitrios Davalos, PhD, associate director of the CIVIR and one of the paper's lead authors. "And when we compared those results to those of a separate, healthy control group of mice, we saw that thrombin activity in the control group was wholly absent."
"Our results are proof of principle that a thrombin-specific molecular probe could be used as an early-detection method," added former Gladstone Postdoctoral Researcher Kim Baeten, PhD, the paper's other lead author.
The team's results offered significant support for the notion that thrombin activity is directly tied to the degradation of nerve cell's myelin sheath -- and the subsequent destruction of nerve cells -- that characterizes MS. But they also shed light on what has been a long-standing mystery: the underlying molecular processes that kick-start the progression of MS.
"In the future," said Dr. Akassoglou, "this thrombin-specific ACPP could be developed to one day allow for early patient diagnosis and therapeutic intervention -- including a way to effectively monitor how patients are responding to the latest treatments."
Dimitrios Davalos, Kim M. Baeten, Michael A. Whitney, Eric S. Mullins, Beth Friedman, Emilia S. Olson, Jae Kyu Ryu, Dimitri S. Smirnoff, Mark A. Petersen, Catherine Bedard, Jay L. Degen, Roger Y. Tsien, Katerina Akassoglou. Early detection of thrombin activity in neuroinflammatory disease. Annals of Neurology, 2013; DOI: 10.1002/ana.24078
Source: ScienceDaily Copyright 2013 by ScienceDaily, LLC (05/12/13)
A protein involved in blood clotting may be a new indicator to help detect multiple sclerosis (MS) lesions before symptoms arise. The presence of the clotting protein, thrombin, signals an early stage of the disease when the blood-brain barrier is breached and the brain’s immune response is set into motion. The research was presented at Neuroscience 2013, the annual meeting of the Society for Neuroscience and the world’s largest source of emerging news about brain science and health.
30,000 scientists are attending this meeting.
“Our research shows this indicator is a promising approach for detecting MS-like lesions early, even before major symptoms appear,” said senior author Katerina Akassoglou, Ph.D., of the Gladstone Institutes and the University of California, San Francisco. “Such sensitive indicators could act as red flags that signal neuroinflammatory changes in the brain not only in MS, but also in other diseases such as Alzheimer’s.”
MS is a debilitating disorder that can be intermittent or progressive, and causes numbness, fatigue, difficulty walking, paralysis, and loss of vision in 2 million people worldwide. MS arises when the body’s immune system attacks its own myelin sheaths, the protective coverings that surround neurons and allow signals to move from one cell to the next.
The researchers found that thrombin, usually a beneficial protein involved in blood clotting, builds up in the central nervous system as MS progresses. Thrombin enters in the brain together with fibrinogen, another clotting protein when the protective barrier between the blood and brain becomes leaky. Thrombin converts the fibrinogen to fibrin which activates brain’s immune cells that break down the protective myelin sheath that surrounds neurons in the central nervous system. Because thrombin levels increase as the disease progresses, the researchers conclude that it could be used as an early detector of the disease.
In their studies, the researchers used a mouse model and demonstrated that MS symptoms increased as thrombin levels rose. Early detection of MS could result in more successful treatment of the disease.
Research was supported with funds from the National Multiple Sclerosis Society, the Nancy Davis Foundation for Multiple Sclerosis, and the National Institutes of Health. Dr. Akassoglou outlined her findings in a press conference held on Sunday, November 10, and this summary was distributed with the press release. The scientific presentation of Dr. Akassoglou’s work will be delivered on Monday, Novermber 11.
Source: Bioquick News (11/11/13)
Biomarkers predict second MS attack(07/10/13)
In patients who experienced a first attack of multiple sclerosis (MS) symptoms, risk of a second attack was associated with a variety of baseline factors, researchers said here.
Measurements of brain lesions with MRI, oligoclonal bands in cerebrospinal fluid (CSF), and visual and sensorimotor evoked potentials were, collectively, indicators for patients at relatively high risk of a second attack within 12 months, reported Vittorio Martinelli, MD, of San Raffaele Hospital in Milan.
And, in a separate pan-European study, levels of the chitinase 3-like 1 (CHI3L1) CSF protein were a moderately strong predictor of second attacks in a similar patient population, said Ester Cantó, a PhD student a Vall d'Hebron University in Barcelona.
Using a cutoff value of 190 ng/mL, patients with higher CHI3L1 values showed a median time to develop clinically definite MS by 2005 McDonald criteria of 12.4 months (95% CI 11.8-13.0), compared with 39.5 months in patients with lower CHI3L1 values (95% CI 29.5-50.4), she said.
Both studies were reported at the European Committee for Treatment and Research in Multiple Sclerosis annual meeting, where attention has been particularly focused on the earliest stages of MS.
To qualify for a diagnosis, patients must have experienced two bouts of symptoms separated in time. A first attack is called clinically isolated syndrome (CIS).
In some patients, years may pass until they experience a second attack and are diagnosed with MS -- or never. Others may experience renewed symptoms in as little as 6 months.
Physicians now want to initiate disease-modifying therapies right away in patients with such aggressive pathology, but currently there are no standards for identifying them.
Martinelli noted that previous studies, using different criteria to stratify patients, have found very different rates of conversion from CIS to MS.
Those studies had established some risk factors for conversion: young age, presence of oligoclonal bands in CSF, past steroid treatment, and large MRI lesion burdens.
But narrowing them to establish a reliable predictive model would be useful, he suggested.
Improved Prediction with Conventional Tests
In a step toward that goal, he and colleagues at San Raffaele examined data collected prospectively from 227 CIS patients seen from 2000 through 2010. The data represented results of standard tests for patients with suspected CIS including MRI scans, CSF analysis for oligoclonal bands, and multimodal (visual and sensorimotor) evoked potential testing.
Mean follow-up was 6.8 years (standard deviation 2.8). Mean time from symptom onset to hospitalization and CIS diagnosis was 1.7 months (SD 1.4).
MRI findings at baseline indicated three-quarters of patients had monofocal lesions, with the remainder showing a multifocal distribution. Total T2 lesion counts were zero or one in 12% of patients, from two to nine in 59%, and 10 or more in 29%. Half the patients had gadolinium-enhancing lesions and 74% had oligoclonal bands in CSF.
Just over 30% converted to clinically definite MS within 2 years; through the entire follow-up, 53% converted.
Statistical analysis showed that three factors were most strongly associated with early conversion to MS:
Having more than two T2 lesions
A positive test for oligoclonal bands in CSF
Being in the top quartile of multimodal evoked potentials (indicating impaired peripheral nerve function)
Among patients lacking these three factors, some 15% converted to MS within 12 months, whereas 40% of those showing all three converted.
"Integration of MRI, CSF, and multimodal evoked potential data is essential for an accurate and personalized risk management in patients with CIS," Martinelli said.
CSF Protein Marker
The study reported by Cantó involved CSF samples and clinical data from 813 CIS patients and 559 controls recruited from 15 centers across Europe. Controls included 121 patients with inflammatory neurological diseases that were not CIS or MS.
Her team focused on CHI3L1 due to its appearance in an earlier proteomics discovery project aimed at finding CSF biomarkers that could distinguish early converters from CIS to MS. The current study was designed to validate those findings in a larger, well controlled sample from multiple centers.
In addition, Cantó said, the researchers wanted to understand more about the origins of CHI3L1 within the nervous system.
CIS patients in the study had provided CSF samples during their diagnostic workups. With mean follow-up of 5.4 years, a total of 60% eventually received an MS diagnosis according to 2005 McDonald criteria and 51.5% by the more restrictive Poser criteria.
Across the entire cohort of CIS patients (irrespective of conversion), mean CHI3L1 levels were higher than those in non-inflammatory neurological disease controls by 70 ng/mL, but lower than those in the controls with inflammatory neurological disease by 329 ng/mL (both P<0.0001).
Levels were higher by 40 ng/mL (95% CI 25-56) in patients who converted to MS during follow-up than in those who didn't (P<0.00001), Cantó said.
CHI3L1 levels remained an independent risk factor (P<0.00001) for early conversion when analyzed in a model that also included age at CIS onset, presence of oligoclonal bands, and so-called Barkhof criteria based on MRI findings.
In addition to predicting early conversion to MS, CHI3L1 levels above 190 ng/mL also predicted more rapid disability progression, Cantó said.
Mean time to expanded disability status scale (EDSS) scores of 3.0 was 156 months in those with high values compared with 215 months in those with low values (P=1×10-9).
A histopathology study, using cells from CSF obtained from five CIS patients and five controls with non-inflammatory neurological disease, showed that CHI3L1 expression was localized in MS-type lesions and reactive astrocytes and other activated immune cells.
Cantó said these latter results suggested that elevations in the marker "reflect the degree of astrocyte activation secondary to inflammation."
Both studies had no commercial funding. Quidel provided assays for CHI3L1 but otherwise played no role in the study by Cantó and colleagues.
Martinelli reported relationships with Biogen Dompe, Merck Serono, Bayer Schering, Teva, and Sanofi. Other investigators in his study had relationships with these firms and Genmab.
Cantó reported no conflicts of interest. Other investigators in her study reported relationships with Bayer Schering, Merck Serono, Biogen Idec, Teva, Sanofi, Novartis, Roche, Elan, Genmab, UCB, Wyeth, and others.
Primary source: European Committee for Treatment and Research in Multiple Sclerosis
Source reference: Martinelli V, et al. "Predicting early conversion to multiple sclerosis in patients with clinically isolated syndromes: the importance of an integrated modeling of risk factors" ECTRIMS 2013; Abstract 155.
Additional source: European Committee for Treatment and Research in Multiple Sclerosis
Source reference:Canto E, et al. "Validation of cerebrospinal fluid chitinase 3-like 1 as a prognostic biomarker of conversion to multiple sclerosis and disease severity in patients with clinically isolated syndromes" ECTRIMS 2013; Abstract 156.
Source: MedPage Today © 2013 MedPage Today, LLC (07/10/13)
A research team lead by Violaine Harris, Ph.D., at the Tisch MS Research Center of New York, has just published findings on a new method of measuring disease activity in patients with multiple sclerosis (MS) (Harris, et al, Cerebrospinal fluid fetuin-A is a biomarker of active multiple sclerosis, Multiple Sclerosis Journal, Epub: 2/25/2013 doi: 10.1177/1352458513477923 ahead of print).
This important biomarker discovery is based on spinal fluid measurement of Fetuin-A levels obtained over the course of several years of clinical and pathological studies of MS patients as well as experimental models of the disease. Dr. Harris's findings are likely to change the process for making treatment decisions in MS patients.
Current MS treatment is designed to stop disease activity in the brain and spinal cord with the goal of arresting disease progression and disability. According to Dr. Saud A. Sadiq, the senior author on the study, "these findings will provide a measurable method of monitoring the effectiveness of treatment much like determining blood sugar levels are assayed for diabetic patients. Many patients with MS on treatment report 'worsening' despite stable MRI findings. Addition of Fetuin-A measurement will help better evaluate disease activity in such patients."
The Tisch MS Research Team continues to study the underlying mechanisms of elevation of spinal fluid Fetuin-A to determine its exact role in multiple sclerosis.
ABOUT TISCH MS RESEARCH CENTER OF NEW YORK For over twenty years, Dr. Saud A. Sadiq has believed that combining excellence in clinical care with innovative research targeted at finding the cure for multiple sclerosis would set an exemplary standard in the treatment of people with MS. Today, the Tisch MS Research Center of New York embodies this new model of healthcare, in which your doctor is also your researcher. Dr. Sadiq helps those with MS by conducting cutting-edge, patient-based research to ensure unparalleled care. The close relationship of the non-profit research center and its affiliated clinical practice (International Multiple Sclerosis Management Practice) enables the testing of new MS treatments and accelerates the pace at which research discoveries move from lab bench to bedside. The Tisch MS Research Center of New York aims to identify the disease trigger, optimize treatments for patients and repair the damage caused by multiple sclerosis.
Source: Tisch MS Research Center of New York & PR Newswire Copyright (C) 2013 PR Newswire (30/07/13)
MicroRNA are small noncoding RNA molecules that are involved in the control of gene expression. To investigate the role of microRNA in multiple sclerosis (MS), we performed genome-wide expression analyses of mRNA and microRNA in T-cells from MS patients and controls.
Methods: Heparin-anticoagulated peripheral blood was collected from MS-patients and healthy controls followed by isolation of T-cells.
MicroRNA and RNA from T-cells was prepared and hybridized to Affymetrix miR 2.0 array and Affymetrix U133Plus 2.0 Human Genome array (Santa Clara, CA), respectively. Verifications were performed with real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA).
Results: We identified 2,452 differentially expressed genes and 21 differentially expressed microRNA between MS patients and controls.
By Kolmogorov-Smirnov test, 20 of 21 differentially expressed microRNA were shown to affect the expression of their target genes, many of which were involved in the immune system. Tumor necrosis factor ligand superfamily member 14 (TNFSF14) was a microRNA target gene significantly decreased in MS.
The differential expression of mir-494, mir-197 and the predicted microRNA target gene TNFSF14 was verified by real-time PCR and ELISA.
Conclusion: These findings indicate that microRNA may be important regulatory molecules in T-cells in MS.
Author: Margareta JernÃ¥sClas MalmestrÃ¶mMarkus AxelssonIntawat NookaewHans WadenvikJan LyckeBob Olsson
Credits/Source: BMC Immunology 2013, 14:32
Source: 7thSpace Interactive © 2013 7thSpace Interactive (30/07/13)
A blood test could one day provide a fast, inexpensive way for multiple sclerosis patients to assess the effectiveness of their medications and track disease flares.
While the test is still years away from market, the new biotechnology may prove invaluable for people with multiple sclerosis (MS), a degenerative disease that affects the brain, spinal cord and optic nerve, causing disability, chronic fatigue and pain, among other symptoms. Currently, doctors and patients rely on MRIs, which are expensive and time-consuming, to evaluate the progress of MS and the effects of treatment.
“You can't just walk in and say, ‘Hey I’m here.’ You have to schedule [the MRI], and somebody has to read it,” said Carolyne Reed, 62, a real estate agent in Tuscon, Arizona who was diagnosed with MS in her late forties.
“I'd rather know sooner rather than later,” Reed added, acknowledging that MRI results take time. “The not knowing, the constant feeling of being in limbo is very, very difficult."
Researchers at the University of California, San Francisco, and the Stanford University School of Medicine have identified a blood biomarker called TOB1 that they believe points to MS disease activity, according to a study published in the June edition of The Journal of Experimental Medicine.
TOB1 is only one MS biomarker out of many possibilities. When the immune system begins to attack the brain or the central nervous system, it creates inflammation, which can be picked up in a blood test. Biomarkers can also point to debris left in the blood after an MS relapse. The more damage inside the body, the stronger the presence of a biomarker on the test.
An Easier Way to Monitor MS?
A biomarker, in the simplest terms, is something that can be precisely measured within the body, said Sergio Baranzini, PhD, a molecular geneticist at the University of California, San Francisco. Biomarkers like cerebrospinal fluid, blood, urine, saliva, stool and tears play a role in diagnosing and tracking a host of illnesses, from strep throat to HIV and cancer.
"All these bodily fluids contain information about a disease process," Dr. Baranzini said. "The trick is to correlate the production of this substance and the disease process that we’re trying to track."
And that's what makes research so challenging a shortage of qualified doctors. A blood test would be simple to schedule at any laboratory and provide faster results.
“A couple weeks is a while to struggle with something and wonder if it's going to be this way forever,” Reed added.
To Be Effective, a Blood Test Must Outperform MRI
In order to make a difference for people with MS, any new blood test must outperform the MRI. If a blood test is less expensive and more convenient, but no more accurate than an MRI, there’s no reason to transfer over, said Thomas Stewart, a physician assistant at Rocky Mountain Multiple Sclerosis Center.
“You got this blood marker showing inflammation? So what?” Stewart said. “That doesn’t really get us very far. We’ve already got some markers for disease activity, you’ve got MRI. You have to be more sensitive than that.”
"The blood biomarkers would be a big advance, [but] it’s a little bit of a pipe dream right now," Dr. Bermel said, agreeing with Stewart's assessment. "Right now we don’t have MS divided into sub-types enough to create a blood test like that."
If it lives up to it’s potential, an MS blood test would reduce some of the financial burden, and the wait time, of treating multiple sclerosis. And though it's not on the market yet, Barazini said the technology should be available within a decade.
“I think it would give you more control over a lot of aspects of your life,” Reed said. “It is very difficult trying to live every day not knowing if the sword is going to fall on your head. This [test] can take some of the unknown out of it.”
Source: Everyday Health Copyright © 2013 Everyday Health Media, LLC (17/07/13)
A study by Hans-Peter Hartung, M.D., of Heinrich-Heine-Universität, Düsseldoft, Germany, and colleagues examines the association between IL-17F and treatment response to interferon beta-1b among patients with relapsing-remitting multiple sclerosis.
Serum samples were analyzed with an immunoassay from 239 randomly selected patients treated with interferon beta-1b, 250 micrograms, for at least 2 years in the Betaferon Efficacy Yielding Outcomes of a New Dose Study. Researchers measured the levels of IL-17F at baseline and month 6, as well as the difference between the IL-17F levels at month 6 and baseline were compared between: (1) patients with less disease activity versus more disease activity; (2) patients with no disease activity versus some disease activity; and (3) responders versus nonresponders.
According to study results, levels of IL-17F measured at baseline and month 6 did not correlate with lack of response to treatment after 2 years using clinical and magnetic resonance imaging (MRI) criteria. Relapses and new lesions on MRI were not associated with pretreatment serum IL-17F levels. When patients with neutralizing antibodies were excluded, the results did not change.
"We found that serum concentrations of IL-17F alone did not predict response to interferon beta-1b therapy in patients with relapsing-remitting multiple sclerosis." The study concludes, "Given the multifaceted pathophysiology associated with disease progression and response to treatment by patients with relapsing-remitting multiple sclerosis, using extreme patient cohorts in combination with immune-based biomarker signatures may actually be the most efficient way of initially identifying response markers."
Source: Science Codex (04/06/13)
The aetiology of multiple sclerosis (MS) remains unknown. This hampers molecular diagnosis and the discovery of bio-molecular markers. Consequently, MS diagnostic procedures are complex and criteria for assessing therapeutic efficacy are controversial, suggesting that a pathophysiological rather than an aetiological approach to the disease would be more appropriate. In this regard, blood-proteomics represents a still-unexplored tool. We investigated the potential of proteomics as applied to peripheral blood mononuclear cells (PBMCs) for differentiating treatment-naive RR-MS patients from healthy controls and from IFN-treated RR-MS patients.
A comparative analysis of PBMC proteins isolated from 13 unselected IFN-treated RR-MS patients, 6 IFN-untreated RR-MS patients and 14 matched healthy controls was performed using two-dimensional gel electrophoresis and MALDI-TOF mass spectrometry. We considered the volume of each spot, expressed as a percentage of the total volume of all spots in the gel. Heuristic clustering was applied to a composite population made up of a random sequence of gels from the different groups in comparison. For the differentially expressed proteins, we applied the Student's t-test to identify only those down- or up-regulated at least 2.5-fold [Ratio(R) >= 2.5] with respect to the homologous spots of the compared groups.
Rho-GDI2, Rab2 and Cofilin1 were found to be associated with down-regulated and naive group phenotypes; Cortactin and Fibrinogen beta-Chain Precursor were found to be associated with down-regulated and group-related IFN-treated RR-MS phenotypes. Thus, by means of similarity analysis, the proteomes were homogeneously segregated into three distinct groups corresponding to naive, IFN-treated and healthy control subjects. Interestingly, no separation was found between IFN-treated and healthy controls. Moreover, the molecular phenotypes were consistent with disease pathogenesis.
We demonstrated for the first time, albeit only with preliminary data, the aprioristic possibility of distinguishing naive and IFN-treated MS groups from controls, and naive from IFN-treated MS patients using a blood sample-based methodology (i.e. proteomics) alone. The functional profile of the identified molecules provides new pathophysiological insight into MS. Future development of these techniques could open up novel applications in terms of molecular diagnosis and therapy monitoring in MS patients.
Roberto De Masi, Sergio Pasca, Rocco Scarpello, Adele Idolo and Antonella De Donno
Provisional Complete Article
Source: BMC Neurology © 2013 BioMed Central Ltd (28/05/13)
Summary: In this study from the US, the researchers investigated if fetuin-A is an indicator of disease activity. Fetuin-A is a serum protein secreted mainly from the liver that functions in a wide variety of physiological and pathological processes. It has recently been identified as a potential biomarker in MS, with many functions, including a role in immune pathways.
The researchers found that fetuin-A levels were reduced in CSF one year post treatment with natalizumab. Interestingly, they found that 69% of natalizumab-treated patients overall had decreased fetuin-A levels, which correlates with the known response rate to natalizumab treatment. Fetuin-A was increased in demyelinating lesions and in grey matter within MS brain tissue. In EAE, they found fetuin-A was elevated in degenerating neurons around demyelinating lesions. Also, fetuin-A deficient mice demonstrated delayed onset and reduced severity of EAE symptoms.
Therefore, this study shows that CSF fetuin-A is a biomarker of disease activity and natalizumab response in MS. It raises the possibility that fetuin-A may play a role in the disease process but this needs to be investigated further.
BACKGROUND: There is an urgent need for biomarkers in multiple sclerosis (MS) that can reliably measure ongoing disease activity relative to inflammation, neurodegeneration, and demyelination/remyelination. Fetuin-A was recently identified as a potential biomarker in MS cerebrospinal fluid (CSF). Fetuin-A has diverse functions, including a role in immune pathways.
OBJECTIVE: The objective of this research is to investigate whether fetuin-A is a direct indicator of disease activity.
METHODS: We measured fetuin-A in CSF and plasma of patients with MS and correlated these findings to clinical disease activity and natalizumab response. Fetuin-A expression was characterized in MS brain tissue and in experimental autoimmune encephalomyelitis (EAE) mice. We also examined the pathogenic role of fetuin-A in EAE using fetuin-A-deficient mice.
RESULTS: Elevated CSF fetuin-A correlated with disease activity in MS. In natalizumab-treated patients, CSF fetuin-A levels were reduced one year post-treatment, correlating with therapeutic response. Fetuin-A was markedly elevated in demyelinated lesions and in gray matter within MS brain tissue. Similarly, fetuin-A was elevated in degenerating neurons around demyelinated lesions in EAE. Fetuin-A-deficient mice demonstrated delayed onset and reduced severity of EAE symptoms.
CONCLUSIONS: Our results show that CSF fetuin-A is a biomarker of disease activity and natalizumab response in MS. Neuronal expression of fetuin-A suggests that fetuin-A may play a pathological role in the disease process.
Authors: Harris VK, Donelan N, Yan QJ
Source: Mult Scler. 2013 Feb 25 and Pubmed PMID: 23439582 (06/03/13)
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.
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.
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)