MS Research Page
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Last updated on SEPTEMBER 29, 2011
Impaired neurosteroid synthesis in multiple sclerosis
Farshid Noorbakhsh1,2 Kristofor K. Ellestad1, Ferdinand Maingat1, Kenneth G. Warren1, May H. Han3,
Lawrence Steinman3, Glen B. Baker4 and Christopher Power1,4,5
1 Department of Medicine (Neurology), University of Alberta, Edmonton, AB T6G 2S2, Canada
2 Department of Immunology, Tehran University Medical Sciences, Tehran, Iran
3 Departments of Neurology and Neurological Sciences, Stanford University, Stanford, CA 943055325, USA
4 Department of Psychiatry, University of Alberta, Edmonton, AB T6G 2G3, Canada
5 Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB T6G 2S2, Canada
Correspondence to: Dr Christopher Power, Department of Medicine (Neurology), 6-11 Heritage Medical Research Centre,
University of Alberta, Edmonton, AB T6G 2S2, Canada E-mail: firstname.lastname@example.org
Received May 6, 2011. Revision received July 15, 2011. Accepted July 18, 2011.
Summary: High-throughput technologies have led to advances in the recognition of disease pathways and their underlying mechanisms. To investigate the impact of micro-RNAs on the disease process in multiple sclerosis, a prototypic inflammatory neurological disorder, we examined cerebral white matter from patients with or without the disease by micro-RNA profiling, together with confirmatory reverse transcriptionpolymerase chain reaction analysis, immunoblotting and gas chromatography-mass spectrometry. These observations were verified using the in vivo multiple sclerosis model, experimental autoimmune encephalomyelitis. Brains of patients with or without multiple sclerosis demonstrated differential expression of multiple micro-RNAs, but expression of three neurosteroid synthesis enzyme-specific micro-RNAs (miR-338, miR-155 and miR-491) showed a bias towards induction in patients with multiple sclerosis (P < 0.05). Analysis of the neurosteroidogenic pathways targeted by micro-RNAs revealed suppression of enzyme transcript and protein levels in the white matter of patients with multiple sclerosis (P < 0.05). This was confirmed by firefly/Renilla luciferase micro-RNA target knockdown experiments (P < 0.05) and detection of specific micro-RNAs by in situ hybridization in the brains of patients with or without multiple sclerosis. Levels of important neurosteroids, including allopregnanolone, were suppressed in the white matter of patients with multiple sclerosis (P < 0.05). Induction of the murine micro-RNAs, miR-338 and miR-155, accompanied by diminished expression of neurosteroidogenic enzymes and allopregnanolone, was also observed in the brains of mice with experimental autoimmune encephalomyelitis (P < 0.05). Allopregnanolone treatment of the experimental autoimmune encephalomyelitis mouse model limited the associated neuropathology, including neuroinflammation, myelin and axonal injury and reduced neurobehavioral deficits (P < 0.05). These multi-platform studies point to impaired neurosteroidogenesis in both multiple sclerosis and experimental autoimmune encephalomyelitis. The findings also indicate that allopregnanolone and perhaps other neurosteroid-like compounds might represent potential biomarkers or therapies for multiple sclerosis.
Apitope vaccine stops MS in its tracks
By Mike Nagle
06/11/2007- UK biopharmaceutical firm Apitope has developed a vaccine that could halt multiple sclerosis in its relentless march to destroy nerve cells.
The drug, called ATX-MS-1467, has now been tested in humans for the first time - in six Secondary Progressive Multiple Sclerosis (SPMS) patients in a Phase I/IIa trial - and the results so far are encouraging. No safety issues have been unearthed and one patient also showed good clinical improvement in their symptoms.
The immune system attacks proteins it sees as dangerous and helps protect us from a myriad of pathogens. Occassionally these attacks can be devastating if it mistakenly sees proteins in our own body as dangerous and sets about destroying them. This autoimmune reaction leads to numerous diseases, such as Type I diabetes.
In the case of MS, the immune system wipes out the myelin sheath around nerve cells - an insulating layer that allows the cells to effectively conduct electrical signals. This causes the nerves to die and the symptoms of MS to appear, including visual problems, weakness, difficulties with balance and speech, severe fatigue, pain, impaired mobility and often disability.
According to the MS International Federation, around 2.5 million people suffer from the incurable, progressive disease.
Current therapies aim to reduce the inflammation around the nerve cells to offset further damage or, alternatively, to suppress the immune system. However, these broad approaches also suffer from significant side-effects such as an increased susceptibility to infections and a greater risk of cancer.
Apitope has taken a different approach with their peptide based vaccine that seeks to retune the immune system so it no longer overreacts to proteins in the myelin sheath. One of these proteins in called myelin basic protein (MBP). This protein is chopped up inside a cell into different peptide strips. Some of these strips or epitopes then bind to a protein called major histocompatability complex (MHC) class II and are carried to the surface of the cell where they are presented to the immune system.
Dr Keith Martin, CEO of Apitope, explained to DrugResearcher.com that if certain danger signals are present, then the MBP peptide epitopes can 'switch on' T cells and cause an inflammatory response that damages the myelin.
However, and this is where the Apitope vaccine comes in, if the epitope is presented to the immune system in the absence of these danger signals, a different subset of T cells are switched on (called regulatory T cells) and instead of causing damage, these can suppress the immune system reaction to the epitope in question and thus make it more 'tolerant' to myelin. They do this through producing interleukin-10 (IL-10), an anti-inflammatory cytokine.
One key part of this is to ensure the vaccine is only injected at sites where there are no danger signals. So, the clinicians doing the trial inject the drug in the periphery of the body and the regulatory T cells produced can then travel to the central nervous system (CNS) and begin to retune the immune system there.
One problem remained however. Not all fragments of MBP are capable of causing the immune system to become tolerant to the protein. For example, the MBP peptide made up of amino acids 89 to 101 can induce an immune response both in terms of priming for T cell reactivity and inducing autoimmune encephalomyelitis (EAE) - the commonly used animal model for MS.
However, the same peptide does not induce tolerance. So which peptides do and which don't? After much research, David Wraith, a Professor of Experimental Pathology at the University of Bristol, found the answer. He discovered that only peptide fragments that are the right size and shape to be presented to the immune system without further processing can go on to induce tolerance. The discovery led to the spin out of the company and also gave it its name and the name of this class of potential drug - Antigen Processing Independent epiTOPES or Apitopes. Prof. Wraith became the chief scientific officer at Apitope.
First, the team use bioinformatics to design peptides that will bind to MHC strongly and, crucially, ones that can also adopt the right shape to bind.
"If the peptide isn't the right shape, then it won't trigger a response," said Martin. "If they are in the right conformation, they won't require processing [and therefore will induce immune system tolerance]."
He added that in the case of MS, Apitope identified five different peptide epitopes that looked like they would work and then proceeded to test them in a number of in vitro assays. After that process, four remained and these are what make up ATX-MS-1467. The advantage to having four is that there are different subtypes of MHC class II molecules and these four can bind to different ones, such that the "vast majority" of MS patients will be theoretically responsive to the drug.
The initial signs are that the vaccine is effective. Given that the myelin sheath also contains other proteins that are thought to induce the immune system to attack, such as myelin oligodendrocyte glycoprotein (MOG), and proteolipid protein (PLP), this is perhaps surprising at first. So how does a vaccine based only on MBP peptides also prevent these other proteins from sending the immune system into overdrive? The answer is 'bystander suppression'. The epitopes for a given protein antigen (in this case MBP) can also induce tolerance to other epitopes from the same antigen, and even epitopes from other antigens, such as MOG and PLP.
"Essentially, the activity of the mixture is greater than the sum of its parts," explained Martin.
Indeed, one patient on the trial has shown "remarkable improvement in her eyesight", explained Prof. Wraith.
"Since the optic nerve is acutely sensitive to inflammation and optic neuritis is often one of the first symptoms of MS, this early indication of efficacy is very encouraging. It suggests that treatment with ATX-MS-1467 can suppress the inflammation associated with MS," he continued.
The next step is to continue to monitor the six patients who have completed dosing in the Phase I/IIa trial so that a three month safety follow-up can be conducted. If the drug gets the all clear, Apitope will then continue with a Phase IIb proof-of-concept trial. If that proves successful, the firm will then look to partner the programme with a larger pharma company, although Martin said the company would be willing to partner earlier if the opportunity arose.
Way before this drug makes it anywhere near the market though, Apitope hope to begin generating revenues thanks to a MS diagnostic test they have developed.
Martin said that early diagnosis in MS is crucial as treatments that seek to slow down or halt the progression of the disease are obviously best given before the disease has had the chance to do too much damage. Even with existing treatments, there is evidence to suggest patients would have much better outcomes if they were diagnosed earlier he said.
Unfortunately, the current process of diagnosing the disease can take a while, leaving patients untreated while the disease damages their nerves. Apitope have developed a blood test that can diagnose the disease much more quickly. The test is still undergoing regulatory tests but Martin said that Apitope hopes it will be available to doctors by the end of 2009. The same test also has the potential to be extended as a tool for other autoimmune diseases such as rheumatoid arthritis and lupus.
Apitope's approach is also applicable to other immune hypersensitivity reactions and the firm has a programme to identify apitopes to prevent Factor VIII inhibitor formation, which can cause haemophilia. Martin said that he is confident the company will gain orphan drug status for this programme from the US Food and Drug Administration (FDA), although they haven't applied for it yet. This is important as the faster regulatory process for orphan drugs means that, if necessary, Apitope could bring that drug to market without a partner.
Scientists at Apitope are also conducting preclinical tests on Type I diabetes and allergy peptides.
The MS project remains the most advanced however, and it is this research that will make or break Apitope's approach to peptide induced tolerance. A great number of people with autoimmune diseases will be waiting with baited breath.
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Discovery of T Cells Making Brain Chemicals May Lead to Better Treatments for Inflammation, Autoimmune Diseases
Released: 9/16/2011 10:35 AM EDT
Source: North Shore-Long Island Jewish Health System
Newswise MANHASSET, NY -- Scientists have identified a surprising new role for a new type of T cell in the immune system: some of them can be activated by nerves to make a neurotransmitter (acetylcholine) that blocks inflammation. The discovery of these T cells is novel and suggests that it may be possible to treat inflammation and autoimmune diseases by targeting the nerves and the T cells. The study was published this week in Science.
The discovery that 2 percent of T cells can make acetylcholine under the control of nerves gives a new insight into how the nervous system regulates immunity, said Kevin J. Tracey, MD, president and chief executive officer of The Feinstein Institute for Medical Research, and principal investigator of the study. The arrival of electrical signals from nerves activates these specialized T cells to produce the acetylcholine necessary to block inflammation, and protect against damage. It is possible to transfer these cells to cross-protect mice from inflammation, and to control these T cells by electrically stimulating the nerves directly.
The present study followed years of work from Dr. Traceys lab that identified the role of the vagus nerve, named for its wandering course from the base of the brain to the liver, spleen and other organs, in blocking inflammation. Applying electrodes to stimulate the vagus nerve blocked the release of tumor necrosis factor (TNF) and other cytokines that underlie the tissue damage in arthritis, inflammatory bowel disease and other syndromes. Stimulating this nerve pathway led to increased production of acetylcholine, a neurotransmitter that binds to the alpha 7 nicotinic acetylcholine receptor. Activating this receptor on macrophages blocked the release of immune molecules (the cytokines,) suggesting a novel strategy for developing anti-inflammatory agents.
But these results raised an important question because the nerve fibers in spleen release norepinephrine, another neurotransmitter, but not acetylcholine. The search for the cells that produce acetylcholine led these investigators to use nude mice, devoid of T cells. Then they examined the spleen cells that make acetylcholine and that led them to a subset of T cells. Transferring these acetylcholine producing T-cells into nude mice restored the vagus nerve circuit that blocked inflammation.
Our results point to a population of acetylcholine-synthesizing memory T cells in spleen that is integral to the function of the inflammatory reflex, the nerve circuit that regulates inflammation and immunity, said Dr. Tracey. It is as if these T cells occupy a nerve-like function in this important circuit.
It should be possible to target these T cells and to modulate this neural circuitry to develop therapeutic modalities for inflammatory and autoimmune diseases. In the future, it may be possible to isolate these T cells and exploit their anti-inflammatory activity. In the meantime, there is a more direct route to use this discovery for therapy. Rheumatoid arthritis patients in Europe are being studied in clinical trials where vagus nerve stimulators are implanted and turned on to stimulate this circuit and suppress inflammation.
Posting of the following article has been approved by The Doctor's Guide to the Internet(TM)
Source: Eur J Vasc Endovasc Surg
Venous Angioplasty in Patients with Multiple Sclerosis: Results of a Pilot Study;Zamboni P, Galeotti R,
Weinstock-Guttman B, Kennedy C, Salvi F, Zivadinov R; European Journal of Vascular and Endovascular Surgery
OBJECTIVES: Chronic cerebrospinal venous insufficiency (CCSVI) is associated with multiple sclerosis (MS). The objective of the study was to see if percutaneous transluminal angioplasty (PTA) of duplex-detected lesions, of the internal jugular and/or azygous veins, was safe, burdened by a significant restenosis rate, and whether there was any evidence that treatment reduced MS disease activity. Design: This was a case-control study. Materials: We studied 15 patients with relapsing-remitting MS and duplex-detected CCSVI. METHODS: Eight patients had PTA in addition to medical therapy (immediate treatment group (ITG)), whereas seven had treatment with PTA after 6 months of medical therapy alone (delayed treatment group (DTG)). RESULTS: No adverse events occurred. At 1 year, there was a restenosis rate of 27%. Overall, PTA was followed by a significant improvement in functional score compared with baseline (p < 0.02). The annualised relapse rate was 0.12% in the ITG compared with 0.66% in the DTG (p = NS). Magnetic resonance imaging (MRI) blindly demonstrates a trend for fewer T2 lesions in the ITG (p = 0.081), corresponding to a 10% decrease in the ITG compared with a 23% increase in the DTG over the first 6 months of the study.
CONCLUSIONS: This study further confirms the safety of PTA treatment in patients with CCSVI associated with MS. The results, despite the significant rate of restenosis, are encouraging and warrant a larger multicentre double-blinded, randomised study.
Multiple sclerosis (MS) is a chronic disease of the central nervous system characterized by inflammation and demyelination.1 It is estimated that MS is diagnosed in more than 10,000 patients every year in the United States alone.2 MS can lead to a wide range of neurologic symptoms including fatigue, headaches, decreased cognition, optic nerve dysfunction, diplopia, decreased balance, extremity weakness, and bladder and bowel dysfunction. The etiology of MS is unknown, although most point to an autoimmune basis at present.3 Many patients with MS receive disease-modifying drugs to prevent relapse and slow disease progression.
Chronic cerebrospinal venous insufficiency (CCSVI) is a recent theory put forth to explain the pathogenesis of MS and its associated symptoms.4 The early work of Charcot and Putnam laid the groundwork for this theory by suggesting the possibility that a relationship existed between the venous drainage from the central nervous system and the lesions associated with MS.5,6 The CCSVI theory states that extracranial venous outflow obstruction (Figure 1A) can lead to venous hypertension and dilatation, which can result in chronic venous reflux,7 prolonged circulatory transit time,8 lower net flow of cerebrospinal fluid,9 and blood brain barrier disruption.10 The latter can potentially cause an infiltration of immune cells (which can cause an autoimmune reaction) and/or red blood cells (which can cause perivenous iron deposition and inflammation) into the central nervous system, both of which may contribute to the development or progression of MS.11
Zamboni et al have described success with treating this condition with angioplasty of the internal jugular (IJ) (Figure 1B) and azygous veins.12 Given the significant motivation on the part of patients suffering from MS to actively seek out treatment options that may address both symptoms and the underlying etiology of this condition, it is not surprising that so much attention has been paid to CCSVI. The purpose of this article is to review the data that are currently available regarding CCSVI and the potential role it may play in the care of patients with MS.
The diagnosis of CCSVI using noninvasive imaging has been one of the challenges associated with this condition. The ultrasound technique described by Zamboni et al has been the most commonly used imaging modality for this purpose.13 This technique involves the evaluation of five different parameters to assess venous flow: reflux in the IJ or vertebral veins, reflux within the deep cerebral veins, evidence of a stenosis within the IJ vein on grayscale images, undetectable flow in the IJ veins, and the absence of the normal decrease in cross-sectional area of the IJ vein when moving from a supine to an upright position.
In a study of 109 MS patients and 177 controls, Zamboni et al found that 47% of measurements were abnormal in the MS patients and only 2.7% were abnormal in the control population. When at least two criteria were used to define a positive examination, the positive and negative predictive values were 100%. Other authors have found an increased prevalence of CCSVI in MS as well, although not to the same extent as Zamboni et al.14-16 This, however, has not been a consistent finding among investigators. For example, Doepp et al found no differences in venous flow between MS patients and healthy controls.17
Although this has led some researchers to conclude that CCSVI is not a true pathologic entity, it has led others to recognize that not every patient with MS has an ultrasound examination consistent with CCSVI. It has been suggested that ultrasound may not be the most effective way to diagnose CCSVI, particularly when specialized training appears to be necessary to optimize the diagnostic accuracy and reproducibility of this technique.18
Magnetic resonance imaging is the standard imaging modality used to both diagnose and follow patients with MS.19 It effectively shows the lesions associated with MS and is a prominent part of the McDonald criteria used to diagnose MS.20 Magnetic resonance venography has been used to detect evidence of venous insufficiency in this population.21 It is believed to be a useful modality for this purpose because it can visualize the actual extracranial venous stenoses while also assessing brain perfusion and iron content within the brain. However, it too has been found to be an inconsistent way to diagnose CCSVI in this patient population.22,23
Most interventionists consider selective venography to be the gold standard for diagnosing CCSVI. Bartolomei et al studied 65 patients and found that all patients had multiple and significant extracranial venous stenoses involving the IJ and/or azygous veins.24 Interestingly, four patterns of extracranial disease were found in these patients: type A (stenosis of the proximal azygous vein with a stenosis of one IJ vein), type B (stenosis of the azygous vein and both IJ veins), type C (stenosis of both IJ veins and a normal azygous vein), and type D (stenosis of the azygous vein with normal IJ veins). These patterns were shown to correlate with the type of MS and the presenting symptoms at the time of MS onset.
At the first meeting of the International Society for Neurovascular Disease held in March 2011 in Bologna, Italy, Denislic reported the results of a study evaluating 65 MS patients with venography and compared the findings with the Expanded Disability Status Scale (EDSS), which is an overall measure of neurologic impairment ranging from 0 (normal neurologic examination) to 10 (death due to MS).25,26 They found that patients with an EDSS score > 6 had significantly more treatable lesions on venography than patients with a lower EDSS score, indicating that the severity of venous disease increases with the severity of the patient’s neurologic condition.
TREATMENT AND RESULTS
Once diagnosed, it is of course important to know whether or not treatment of this condition leads to a significant change in the clinical condition of the patient. In the initial pilot study Zamboni et al performed venography on 65 MS patients with CCSVI diagnosed on ultrasound.12 Patients with a stenosis > 50% in severity were treated with angioplasty using 10- to 12-mm balloons in the IJ veins and 8- to 10-mm balloons in the azygous vein. The relapsing-remitting patients in this group had sustained clinical improvement based on the Multiple Sclerosis Functional Composite; only limited improvement was seen in patients with primary and secondary progressive MS.
The Multiple Sclerosis Functional Composite tests upper extremity dexterity with a timed 9-hole peg test, leg/walking function with a timed 25-foot walk, and cognitive function with a Paced Auditory Serial Addition Test.27 In addition, all of the relapsing-remitting patients with continued venous patency at 18 months were relapse free, leading some to conclude that angioplasty may affect disease progression. Unfortunately, the primary patency rate at 18 months was 53% in the IJ vein, but it was 96% in the azygous vein.
Since this initial study, other reports have emerged about the outcomes after angioplasty in this patient population. Malagoni et al studied 35 MS patients with significant fatigue and found sustained improvement in fatigue and a greater ability to perform daily activities after angioplasty.28 At the International Society for Neurovascular Disease meeting, Zarebinski reported on the results from a study of 420 MS patients treated with angioplasty and found significant improvement in fatigue but no significant improvement in EDSS score or the MS Impact Scale-29.29 Mehta also reported the results from a study of 150 patients with MS. They found significant improvements in quality of life and fatigue after angioplasty.30 In addition, they reported a technical success rate of 77% (defined as < 20% residual stenosis) and a reintervention rate of 9%.
In the original study by Zamboni et al, the reported complication rate was extremely low, with only six patients reporting a self-limited postprocedure headache.12 Since that time, two other studies have specifically reported the complications associated with venous angioplasty and stent placement to treat CCSVI. Ludyga et al retrospectively reviewed 344 procedures performed in 331 patients and Mandato et al retrospectively reviewed 257 procedures in 240 patients.31,32 The complications reported in these papers are outlined in Table 1. Severe complications that have been reported include cardiac arrhythmias, stress-induced cardiomyopathy, adverse drug events (including an intracerebral hemorrhage secondary to anticoagulation), and intracardiac stent migration in the setting of stent placement.31-33
At the present time, anecdotal reports continue to surface about the positive changes reported by patients after endovascular treatment of stenoses within the IJ and azygous veins. However, one can in no way state that enough research has been done to conclude that CCSVI is a true pathologic entity occurring with an increased frequency in MS patients, that this entity is responsible for the symptoms and disease progression seen with MS, and that treatment significantly improves the quality of life in these patients. As a result, additional research is going to be critically important moving forward.
This sentiment was echoed in the recent report from the Research Consensus Panel convened by the Society of Interventional Radiology Foundation, which supported the need for additional well-designed studies in areas including basic science work to better understand the relationship between venous stenoses, hypertension, and CCSVI; single-center studies to define appropriate patients to treat and develop standardized procedural technique; and multicenter, prospective, randomized trials to demonstrate efficacy.34 Ongoing studies include registries in Europe and the United States as well as several prospective single-arm and randomized, blinded studies. Ultimately, these studies will help grow our understanding of CCSVI and help determine what role treatment of this entity can and should play in the care of patients with MS.
Gary Siskin, MD, is Professor and Chairman, Department of Radiology at Albany Medical Center in Albany, New York. He has disclosed that he holds no financial interest related to this article. Dr. Siskin may be reached at (518) 262-2397; email@example.com.
Kenneth Mandato, MD, is Assistant Professor of Radiology, Department of Radiology at Albany Medical Center in Albany, New York. He has disclosed that he holds no financial interest related to this article.
Meridith Englander, MD, is Assistant Professor of Radiology, Department of Radiology at Albany Medical Center in Albany, New York. She has disclosed that she holds no financial interest related to this article.
Chronic Cerebrospinal Venous Insufficiency in Multiple Sclerosis Patients-- By Gary Siskin, MD
There is speculation that CCSVI may contribute to the symptoms experienced by MS patients, but what do the data tell us so far?
July 30, 2011
By Gary Siskin, MD; Kenneth Mandato, MD; and Meridith Englander, MD
CCSVI: What We Need to Know Now and in the Future --- By Michael D. Dake, MD
July 30, 2011
Multidisciplinary collaboration is a necessary step toward answering the many questions about the relationship between MS and extracranial venous obstruction.
By Michael D. Dake, MD
Over the last 2 years, most interventionists have become familiar with the term CCSVI (chronic cerebrospinal venous insufficiency). They share in common a passing exposure to the postulated concept of an association between venous obstruction to drainage of the brain and spinal cord and multiple sclerosis (MS), but most lack firsthand experience evaluating or treating CCSVI. Many are aware of the frequently contentious and inflamed public discussions among groups of interested parties, including neurologists, MS patients and their families, interventionists, federal officials, etc., and thus have decided to observe the drama rather than join the heated fray.
In discussions around the world in cath labs, angio suites, operating rooms, neurology departments, and MS clinics on patient social networks; in feature pages of prominent newspapers and magazines and programming of mainstream media outlets; and at local, national, and international medical meetings, the proposed relationship between MS and extracranial venous obstruction is examined, questioned, but always debated. Everyone wants to learn more.
Everyone wants to understand: What do we know and what don’t we know about CCSVI?
WHAT WE NEED TO KNOW
As all involved focus on these two unknowns, it may prove pragmatically more relevant at this early stage of our fundamental knowledge to consider: What do we need to know? Or posed in another way: What is necessary to establish before it is reasonable to embark on large-scale controlled, multi-institution, randomized trials of CCSVI treatment capable of demonstrating or disproving a link between MS and venous obstruction?
When considering the inability over the last 150 years to definitively grasp the underlying cause of MS, the conceptual difficulties that persistently challenge our understanding of the interplay between anatomical and physiological factors that contribute to symptomatic venous obstruction of other vascular territories, and the difficult-to-comprehend roles of a variety of conditions that apparently portend a predisposition to developing MS, it is unlikely that the CCSVI theory will lend itself to easy pathophysiological examination. Paradoxically, it may prove easier to move forward with CCSVI treatment studies that incorporate established objective endpoints accepted by MS neurologists rather than pursue unproven evaluations of specific but possibly irrelevant physiological consequences of venous flow disturbances.
SKEPTICISM AND CRITICISM
It is understandable that the vast majority of neurologists who deal with MS patients are highly skeptical of CCSVI. Most neurologists have lived through a series of unproven and even dangerous pseudotherapies that prey on the vulnerability and hope-seeking nature of patients with an incurable, progressively disabling disease. From snake venom, to bee stings, and hyperbaric oxygen, etc., neurologists are especially sensitive to potential scams that have plagued the MS landscape, while at the same time consciously aware that many patients are marginally satisfied by their response to the “effective” approved pharmacological therapies.
Despite the current criticism of CCSVI and the recognition that most conversations on the subject between neurologists and interventionists don’t always go well, there is experience that is providing data and evidence to support future randomized controlled treatment trials. Undoubtedly, one of the foremost issues to be addressed is the risk to patients of any CCSVI treatment procedure. Fortunately, the safety of currently practiced endovascular therapy—predominantly percutaneous balloon angioplasty (PTA), is the one area where a substantial fund of data is available from the estimated 13,000 to 15,000 patients treated to date worldwide.
Multiple large patient series published in the medical literature document that any serious complications from PTA of jugular and azygous veins are exceedingly rare.1-5 Untoward effects that are encountered are not dissimilar from adverse events known to accompany balloon dilation of lesions in other venous territories. Establishment of a safety profile for endovascular treatment of CCSVI that is consistent in these reports is a very important step forward and the demonstration of only mild side effects in a minority of patients is critical to advancing further study.
THE FUTURE OF CCSVI
So, as we are poised at this snapshot in time, ready to advance to the next chapter of the CCSVI story—one that will hopefully include genuinely collaborative, multidisciplinary controlled treatment trials with randomized designs and meaningful objective efficacy endpoints—it is important to think about the future and what we would like to know. From this perspective, we can focus on the long list of questions that we hope future trials will bring us closer to answering. In terms of CCSVI diagnosis, treatment, and follow- up, some of the interesting unresolved issues are noted in the Questions Concerning Diagnosis and Treatment and Questions Concerning Posttreatment and Follow-Up sidebars.
In addition to this abridged list of questions are three of the most fundamental issues yet to be understood: What is the endovascular treatment of venous obstruction really affecting—is it flow or something else? Is there any evidence that the trajectory of disease progression is altered after CCSVI treatment? Finally, how can interventionists engage MS neurologists in a nonthreatening, meaningful collaboration to study a concept they regard as total lunacy?
Addressing these and other concerns will sternly test the resolve, patience, and willingness of all concerned individuals to engage in multidisciplinary collaborations to better understand the nature of CCSVI and potentially benefit the lives of MS patients.
Michael D. Dake, MD, is Thelma and Henry Doelger Professor (III), Department of Cardiothoracic Surgery, Stanford University School of Medicine and Falk Cardiovascular Research Center in Stanford, California. He has disclosed that he holds no financial interest related to this article. Dr. Dake may be reached at firstname.lastname@example.org.
Safety profile of endovascular treatment for chronic cerebrospinal venous
insufficiency (CCSVI) in patients with multiple sclerosis.
June 18, 2011
Petrov I, Grozdinski L, Kaninski G, Iliev N, Iloska M, Radev A.
Cardiology Department, Tokuda Hospital Sofia, Bulgaria.
Abstract Purpose: To evaluate the safety of endovascular treatment of chronic
cerebrovascular insufficiency (CCSVI) in patients with multiple sclerosis (MS).
Methods: In a 1-year period, 461 MS patients (261 women; mean age 45.4 years,
range 21-79) with CCSVI underwent endovascular treatment of 1012 venous lesions
during 495 procedures [34 (6.9%) reinterventions]. While balloon angioplasty was
preferred, 98 stents were implanted in 76 patients for lesion recoil, restenosis,
or suboptimal dilation. The procedures were analyzed for incidences of major
adverse events (death, major bleeding, or clinical deterioration of MS), access
site complications, procedure-related complications, and procedural
safety-related variables (fluoroscopy and contrast times). The complication rates
were compared to published data for similar endovascular methods. Results: There
were no deaths, major bleeding events, or clinical deterioration of MS. Access
site complications included limited groin hematoma (5, 1.0%); there were no
arteriovenous fistulas or puncture site infections. Systemic complications
included only rare cardiac arrhythmias (6, 1.2%). Procedure-related complications
included vein rupture (2, 0.4%), vein dissection (15, 3.0%), acute
in-stent/in-segment thrombosis (8, 1.6%), and acute recoil (1, 0.2%); there was
no stent migration or fracture or distal embolization. Mean fluoroscopy time was
22.7 minutes, and mean contrast volume was 136.3 mL.
therapy appears to be a safe and reliable method for treating CCSVI. Innovations
such as purpose-specific materials and devices are needed, as are case-controlled
and randomized data to establish efficacy in ameliorating MS symptoms.
Functional Treatments in Multiple Sclerosis
Courtney AM, Castro-Borrero W, Davis SL, Frohman TC, Frohman EM;
Current Opinion in Neurology (Mar 2011)
Source: Curr Opin Neurol
PURPOSE OF REVIEW: This review focuses on recent advances in the understanding and management of symptoms and dysfunctions associated with multiple sclerosis (MS).
RECENT FINDINGS: A broad spectrum of dysfunctions associated with MS are under investigation. Research published in the past year and a half addresses gait dysfunction, exercise training, fatigue, bowel/bladder and sexual dysfunction, and sleep disruption. Functional electrical stimulation and strength training have been validated for improvement in gait and motor function. Exercise training has been shown to benefit mood and quality of life scores and to reduce circulating inflammatory cytokine levels. Fatigue remains a challenging problem with incremental improvements in understanding of underlying causes and effective drug therapies offered by recent work. Treatment of bowel, bladder and sexual dysfunction utilizing a variety of modalities has been investigated with some progress.
SUMMARY: In the absence of treatments to reverse neurologic injury due to MS, effective symptom management and functional improvement remain essential to mitigate disability and maintain quality of life. Basic research, as well as controlled clinical trials, in this realm offers promising insights and solutions.
Chronic Cerebrospinal Venous Insufficiency (CCSVI) is a newly documented vascular condition that may profoundly change the way we think about MS.
While we are just beginning to understand the link between CCSVI and MS, compelling new research supports further investigation. This site addresses critical aspects of CCSVI, from theory to research to treatment, providing original analysis and discussion that should engage both newcomers and medical professionals alike.
For those just learning about CCSVI, we encourage you to begin in our Basics section for a pragmatic introduction to key aspects of CCSVI theory and treatment. For physicians, researchers, and patients looking for more sophisticated analysis, we hope you enjoy our Advanced Topics section, where all content has been reviewed and vetted by a world-class team of medical professionals whose expertise ranges from neurology to interventional radiology to imaging and physics.
We understand, however, that patient and physician interests run beyond pure research and hard facts. Accordingly, we have provided a dedicated section on Patient Perspectives, including patient experiences during and after CCSVI treatment, and questions and answers for potential patients. Our Helping Yourself section summarizes practical approaches to maintaining vascular health, as well as tips for talking to physicians about CCSVI.
Our aim is to provide MS patients, caregivers, and medical professionals with a definitive resource for learning (more) about CCSVI - the science, the process, and the patient experience. As more research emerges, replacing mysteries with data and speculations with fact, we will be here, objective and clear. Opening veins, opening minds. Let's get started!
- CCSVI Alliance
CCSVI Alliance is a 501(c)(3) nonprofit corporation. While our work may be of interest to people worldwide, our focus is on CCSVI in the United States.
Characterizing iron deposition in multiple sclerosis
lesions using susceptibility weighted imaging.
Haacke EM, Makki M, Ge Y, Maheshwari M, Sehgal V, Hu J, Selvan M, Wu Z, Latif Z,
Xuan Y, Khan O, Garbern J, Grossman RI.
Department of Radiology, Wayne State University, Detroit, Michigan 48201, USA. email@example.com
PURPOSE: To investigate whether the variable forms of putative iron deposition seen with susceptibility weighted imaging
(SWI) will lead to a set of multiple sclerosis (MS) lesion characteristics different than that seen in conventional MR
MATERIALS AND METHODS: Twenty-seven clinically definite MS patients underwent brain scans using magnetic resonance imaging
including: pre- and postcontrast T1-weighted imaging, T2-weighted imaging, FLAIR, and SWI at 1.5 T, 3 T, and 4 T. MS
lesions were identified separately in each imaging sequence. Lesions identified in SWI were reevaluated for their iron
content using the SWI filtered phase images.
RESULTS: There were a variety of new lesion characteristics identified by SWI, and these were classified into six types.
A total of 75 lesions were seen only with conventional imaging, 143 only with SWI, and 204 by both. From the iron
quantification measurements, a moderate linear correlation between signal intensity and iron content (phase) was
CONCLUSION: The amount of iron deposition in the brain may serve as a surrogate biomarker for different MS lesion
characteristics. SWI showed many lesions missed by conventional methods and six different lesion characteristics. SWI was
particularly effective at recognizing the presence of iron in MS lesions and in the basal ganglia and pulvinar thalamus.
CCSVI At Hubbard fMRI Institute
Here is the link to the Main Research Page
CCSVI and the Brain
Multiple Sclerosis Venous Insufficiency (CCSVI) Protocol
The Hubbard Foundation is a member of the National Center for Excellence in MRI (NICE), consortium of MRI centers around the
world to evaluate venous outflow from the brain and neck of patients with MS. The chronic cerebrospinal venous insufficiency
(CCSVI) theory has been proposed by Dr. Zamboni in Italy and Dr. Mark Haacke of Wayne State University in Detroit and McMaster
University in Toronto. According to their evidence, the brain and neck veins of MS patients may be clogged leading to iron
deposits in the cerebral veins and allowing immune cells to wiggle out of the blood into the brain tissue where they attack
myelin. Ultrasound is able to visualize large veins in the neck but MRI venography is able to evaluate smaller veins in the
Fingolimod 3-Year Results Show Continued Low
Relapse and Disease Activity in MS
Susan Jeffrey April 25, 2008 (Chicago) — Results from the 3-year extension of an earlier randomized trial of FTY720, or fingolimod (Novartis), a still-investigational oral treatment in patients with relapsing-remitting multiple sclerosis (RRMS), show continued low rates of relapse and disease activity on magnetic resonance imaging (MRI), researchers report.
Results of the extension study, funded by Novartis Pharma AG, were presented here at the American Academy of Neurology 60th Annual Meeting.
"In conclusion, here we have a drug that is an oral drug, and this is a very important point to underline" for patients, Giancarlo Comi, MD, from Vita-Salute San Raffaele University, in Milan, Italy, told a press conference here. "The drug, based on the data that we have, seems to be active even for the extended 3-year period tested in this type of clinical trial, and it seems that the safety profile, at least as far as we know today, is not presenting any major problems."
An Oral Alternative
Currently approved treatments for MS are the immune-modulating agents beta interferon and glatiramer acetate, which reduce relapse rates by about 30%, the authors note. However, both types of drugs are given either intramuscularly or subcutaneously, and interferons are associated with systemic reactions in some 60% of patients, with implications for adherence to treatment.
Fingolimod is a still-investigational drug that, given orally, acts as a superagonist to sphingosine-1-phosphate (S1P) receptors on the surface of thymocytes and lymphocytes, causing them to be sequestered in secondary lymph organs. This reduces the overall number of circulating lymphocytes available to mount an autoimmune reaction to the myelin sheath surrounding axons in MS. The phase 2 study was a double-blind, placebo-controlled proof-of-concept study that randomized 281 patients with relapsing MS to 1 of 3 treatment groups — 1.25-mg oral fingolimod, 5.0-mg oral fingolimod, or placebo — for 6 months (the core study). The primary end point was the total cumulative number of gadolinium-enhancing lesions on 6 postbaseline MRI scans. Other MRI parameters and clinical parameters were also evaluated. Of 281 randomized patients, 255 completed the 6-month core study. The most common reasons for premature discontinuation were adverse events and withdrawal of consent, the authors note. In their report of the primary results, published in 2006 in the New England Journal of Medicine, the authors showed that the median number of enhancing lesions on MRI — indicative of active disease — was significantly reduced with fingolimod treatment compared with placebo. Although the study was not powered to detect a treatment effect on clinical relapse-related end points, the authors pointed out that there were significant improvements in the annualized relapse rate with both fingolimod doses (reduced by 53% in the 5.0-mg group and 55% in the 1.25-mg group) compared with placebo (Kappos L et al. N Engl J Med. 2006;355:1124-1140). They then carried out a long-term extension study, where patients who had received placebo in the core study were randomized again to 1 of the 2 fingolimod doses. Of the 255 patients who completed the core study, 250 entered the extension. Investigators and patients remained blinded during this phase to their original treatment assignment.
Results of the first 6 months of that extension study with oral fingolimod in patients with RRMS, published in the original report, continued to show low levels of disease activity on MRI as well as low relapse rates in patients who received the drug continuously through 12 months. The group of patients who had been receiving placebo during in the core study and were switched to active drug in the extension showed marked reduction in disease activity on MRI and clinical relapses after 6 months on fingolimod compared with the 6 months on placebo.
National Multiple Sclerosis Society Launches Drug Development Initiative
Fast Forward Program Will Bridge the Gap Between University Research and Drug Development, Speeding New Treatments for People With MS
New York, NY November 27, 2007 - The National Multiple Sclerosis Society today announced the creation of Fast Forward, a technology-transfer initiative aimed at translating promising laboratory discoveries into effective new treatments for multiple sclerosis.
Fast Forward will identify, evaluate and partner with start-up and existing companies to develop novel therapies or repurpose existing drugs for the treatment of multiple sclerosis. Fast Forward, a wholly owned subsidiary of the National Multiple Sclerosis Society, is currently evaluating business proposals and plans to make initial investments in early 2008.
The National MS Society is one of only a handful of health-related nonprofit organizations in recent years to create technology-transfer programs, driven in part by the lack of progress in drug development for certain diseases. Other examples include the Cystic Fibrosis Foundation and the Leukemia and Lymphoma Society.
Timothy Coetzee, executive director of Fast Forward, said some private corporations are hesitant to invest the time and money needed to develop MS-related treatments because the potential market is considered relatively small. The worldwide market for MS-related therapies is estimated at $4 billion annually, with just six drugs currently available for people with multiple sclerosis.
“It is our responsibility to find innovative and effective ways to fill the gap between university knowledge and commercial treatments and to meet our commitment to people with MS,” Coetzee said. “We won't hit homeruns on every investment, but when we do, it will change the future for people living with this disease.”
Fast Forward has already secured $4.5 million of the $30 million it plans to raise during the next six years to fund the investments. Fast Forward expects revenue from the program, generated from royalty and milestone payments achieved from the successful development and commercialization of treatments.
“There is no easy answer to finding treatments for MS, but the answers are there and Fast Forward can help us find them,” said Howard Weiner, a neurologist at Harvard Medical School . “This is an important step in finding better treatments for this disease.”
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 will accomplish 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. http://www.fastforward.org
NEW MS VACINE! STOPS MS IN IT'S TRACKS!
Autoimmune Disease Vaccine Safe, Potentially Beneficial in MS
Medscape Medical News 2007. © 2007 Medscape
August 15, 2007 — A newly developed DNA vaccine for multiple sclerosis (MS) is safe and appears to produce beneficial brain and immune system changes in patients with moderate disease.
In the first-in-human trial of a DNA vaccine to treat autoimmune disease, investigators found BHT-3009 (Bayhill Therapeutics, Palo Alto, California), a tolerizing vaccine encoding full-length human myelin basic protein (MBP), induced antigen-specific immune tolerance with concordant reduction of inflammatory brain lesions on brain magnetic resonance imaging (MRI).
""We were able to downregulate the immune system in an antigen-specific way. The reason this is important is that MS, like other autoimmune diseases, is caused by antigen-specific T-cells that attack the myelin. Unlike most other MS therapies, BHT-3009 targets only disease-causing cells, and therefore the hope is that it will be a safer, better-tolerated treatment than other MS drugs," principal investigator Hideki Garren, MD, PhD, from Stanford University, in Palo Alto, and Bayhill Therapeutics, told Medscape.
The study is published online August 13 in the Annals of Neurology.
Turning Off Immune Response
While DNA vaccines have been around for almost 20 years and have been tested in clinical cancer and infectious disease trials, the results have been "somewhat disappointing," said Dr. Garren.
"These vaccines have not worked out exactly as expected and have failed in the sense that they have not met an approvable end point. However, they have shown that they can achieve some immune response in humans," he said.
While DNA vaccines for cancer and infectious diseases have sought to activate the immune system, Dr. Garren and his colleague Lawrence Steinman, MD, also from Stanford University, took the opposite approach and developed a vaccine that has been shown in animal models of autoimmunity to downregulate or alter ongoing immune response.
"In cancer and infectious disease, the aim is to mobilize, or turn on, the immune system to fight the disease. But with autoimmune diseases like MS, the immune system is overactive. We thought perhaps the potential of DNA vaccines lies not in their ability to activate the immune system but to turn it off, and so we invented this [DNA] vaccine and were able to demonstrate that it worked in animals," he said.
Dr. Garren said MS was chosen as the candidate disease because it has a well-defined antigen — MBP — and so the researchers designed the vaccine to encode for MBP.
Conducted in 4 centers in Canada and the United States, the phase 1/2 randomized, double-blind, placebo-controlled trial included 30 MS patients age 18 years and older with relapsing-remitting MS (RRMS) or secondary progressive MS (SPMS) who were not taking any other disease-modifying agents.
Trial eligibility criteria also required patients have either 1 to 5 gadolinium-enhancing lesions on MRI, a relapse in the previous 2 years, or disease worsening in the previous 2 years. In addition, subjects had a screening disability score on the Kurtzke Expanded Disability Status Scale (EDSS) between 2.5 and 6.5 inclusive.
A total of 11 patients with RRMS, 13 with SPMS without relapses, and 6 patients with SPMS with relapses were enrolled in the trial.
Patients were enrolled in 1 of 3 study groups: placebo, BHT-3009 alone, or BHT-3009 plus atorvastatin calcium. Subjects were also divided into 3 BHT-3009 doses of 0.5 mg, 1.5 mg, or 3 mg per dose.
No Benefit With Atorvastatin Combo
According to the paper, the combination BHT-3009/atorvastatin group was added based on preclinical research demonstrating that atorvastatin alone can treat animal models of MS by promoting helper T-cell subtype 2 deviation of the autoimmune response.
The study's primary end point was safety determined by the number of adverse events, neurologic assessments of relapses and disability, MRI measurement of gadolinium-enhancing and T2 lesions, and standard laboratory evaluation of hematological, renal, and liver function.
Secondary outcomes included the number and volume of gadolinium-enhancing lesions on MRI, relapses, and analysis of antigen-specific immune responses.
BHT-3009 was administered intramuscularly at weeks 1, 3, 5, and 9. Oral atorvastatin calcium was given at a dose of 80 mg once daily, starting 2 days prior to the first BHT-3009 dose and continuing until the treatment blind was broken at week 13.
According to Dr. Garren, the vaccine was safe and well tolerated. The percentage of patients who experienced adverse events, which included gastrointestinal upset, fatigue, and weakness, among others, was no greater in the BHT-3009 study groups vs the placebo group.
In addition, researchers found no substantial benefit of the atorvastatin combination compared with BHT-3009 alone.
"We found the vaccine was safe and well tolerated but, more important, we demonstrated in this small number of patients that the vaccine did not worsen the disease or [brain] MRI activity," said Dr. Garren.
In addition, there were no statistically significant increases in the number or volume of brain lesions. Furthermore, the study showed a trend toward a reduction in lesion activity relative to placebo.
"This was not one of the study end points but rather an unexpected bonus that we were able to attain," he said.
Although it did not reach clinical significance, it is an encouraging finding and suggests BHT-3009 therapy may have the ability to modify underlying disease processes, resulting in a potential stabilization of clinical disease. However, he added, this hypothesis still needs to be tested in a much larger clinical trial.
Currently, the researchers are conducting a randomized, placebo-controlled clinical trial of BHT-3009 in 290 MS patients, the results of which will be available in early fall 2007.
The study was funded by Bayhill Therapeutics Inc. Dr. Garren discloses he is cofounder of and has received salary stock and/or stock options from Bayhill Therapeutics.
Ann Neurol. Published online August 13, 2007.
Research identifies new genes linked with MS July 29, 2007
By Julie Steenhuysen Sun Jul 29, 1:04 PM ET
CHICAGO (Reuters) - After decades of dead ends, scientists have identified two genes that may raise the risk of multiple sclerosis, lending insight into the causes of the debilitating disease.
The findings, released in two medical journals on Sunday, represent the first genes conclusively linked to multiple sclerosis in more than 20 years, experts said.
MS is a disease of the central nervous system that affects about 350,000 people in the United States and more than 2.5 million people globally.
In a large-scale study appearing in an online version of the New England Journal of Medicine, teams of international researchers scanned the entire human genome of more than 12,000 people for MS risk factors.
That study uncovered two new gene suspects, both of which are thought to play a role in autoimmune disease.
Until now, the only genetic link identified with MS was the major histocompatibility complex, or MHC, a large cluster of genes essential to the immune system.
Neither of the newly discovered genes appears to be as instrumental to developing the disease as MHC, but the research is important because it lends insight into other genetic factors that raise a person's risk of multiple sclerosis.
"Having this genetic road map will be of incredible importance in developing new therapies," said Dr. David Hafler of Harvard Medical School, who worked on the genome study.
The role of one of the gene suspects in MS -- a variant of the interleukin-7 or IL-7 receptor -- was confirmed in two papers published online on Sunday in Nature Genetics.
The gene helps control the activity of regulatory T cells, which suppress the activation of the body's immune system.
"This discovery brings us into a whole new pathway that could have a very important role in understanding the fundamental mechanisms that trigger MS," said Dr. Stephen Hauser, professor of neurology at University of California San Francisco, who worked on studies released online in the New England Journal of Medicine and Nature Genetics.
While the studies used different methods, they both pointed the finger at IL-7.
The Nature Genetics study, led by Jonathan Haines of Vanderbilt University Medical Center in Nashville, Tennessee, and Margaret Pericak-Vance of the University of Miami, examined variants in three genes suspected to have a role in the disease. It found variants in IL-7 receptors were consistently more common in MS patients than in healthy people.
Researchers observed a similar association in a separate study in Nature Genetics by Jan Hillert of the Karolinska Institutet in Stockholm and colleagues, who looked at a large collection of people from Denmark, Finland, Norway and Sweden.
The other gene identified by the whole genome scan -- the IL-2 receptor -- has been linked to two other autoimmune diseases: type 1 diabetes and autoimmune thyroid disease.
"The story here is the commonality of autoimmune disease," Hafler said.
Researchers believe both environmental and genetic factors play a role in the development of MS, which attacks and destroys the insulation along nerve fibers.
MS symptoms range from mild muscle weakness to partial or complete paralysis.
From Irwin Mortman - Protein's role in MS June 16, 2007
Stanford researchers clarify protein's role in multiple sclerosis
STANFORD, Calif. — A protein found primarily in the lens of the eye could be the critical “tipping point” in the spiral of inflammation and damage that occurs in multiple sclerosis, researchers at the Stanford University School of Medicine report. This protein—alphaB-crystallin—is not normally found in the brain, but develops in response to the injuries inflicted on nerve cells by multiple sclerosis. The nerve-cell injuries can cause people to suffer loss of motor control and even paralysis.
(Media-Newswire.com) - STANFORD, Calif. — A protein found primarily in the lens of the eye could be the critical “tipping point” in the spiral of inflammation and damage that occurs in multiple sclerosis, researchers at the Stanford University School of Medicine report.
This protein—alphaB-crystallin—is not normally found in the brain, but develops in response to the injuries inflicted on nerve cells by multiple sclerosis. The nerve-cell injuries can cause people to suffer loss of motor control and even paralysis.
“The big breakthrough in this paper is answering the question ‘What is alphaB-crystallin doing?’” said Lawrence Steinman, MD, professor of neurology and neurological sciences. Steinman and his team demonstrated that the protein plays a protective role in a mouse model of multiple sclerosis—and when injected in mice, it can reverse paralysis. Their findings are published in the June 13 advance online edition of Nature.
In multiple sclerosis, the immune system launches an attack against the myelin sheath surrounding nerve cells, causing them to misfire. According to the Multiple Sclerosis Foundation, up to 500,000 people in the United States have been diagnosed with the condition, which causes varying symptoms depending on the location and extent of the scarring of the myelin sheath. Common symptoms include fatigue, weakness, vertigo, numbness and vision problems.
For reasons not yet understood, the immune system considers the expression of the alphaB-crystallin protein in the brain a danger signal and attacks this healing substance. “Like a runaway truck careening down a mountain and then having the brakes fall off, the immune attack against alphaB-crystallin worsens the situation,” said Steinman. And remarkably, he noted, addition of that protein works like restoring the failing brakes, returning control.
If the same recovery is seen in humans, the protein might someday be used to treat multiple sclerosis. “It is a real delight to see that the same material that is naturally produced, that has these protective effects, could potentially be harnessed and used as a therapeutic itself,” said Steinman.
The team is optimistic about the protein being used as a therapy, but Steinman and Shalina Ousman, PhD, a postdoctoral researcher in his laboratory and the first author of the publication, emphasized that it is still a long way from being tested in humans.
The recognition of this protein’s role in multiple sclerosis began more than a decade ago, when Dutch researcher Johannes van Noort, PhD, found that the main stimulant of the immune system’s attack on the brain was not the presumed culprit of one of the parts of myelin, but alphaB-crystallin, the major structural protein of the lens of the eye.
“For some reason, the protein gets turned on in the brain where it’s not expected to be,” said Steinman, who wrote an editorial about van Noort’s finding in 1995 when it was published in Nature. Since then, Steinman and others in the field wondered what it means that a protein normally found in the lens of the eye suddenly appears in the brain. In 2001, Steinman published work in Science cataloging the proteins most abundant in multiple sclerosis, and found that alphaB-crystallin ranked first.
This finding led him and his colleagues to perform a series of experiments on the mouse model of multiple sclerosis—experimental autoimmune encephalomyelitis. They showed in a variety of ways how alphaB-crystallin in mice decreases inflammation and reduces other pathological conditions associated with multiple sclerosis, such as cell death. Also, they demonstrated that the removal of the protein increased the neurological symptoms in the mice.
“We have to remember that repair mechanisms normally exist in response to injury and stress,” said Ousman. “In some cases however, those repair mechanisms fail to overcome the injurious responses. It is important to ask why these mechanisms fail and could their protective function be restored.”
When they gave injections of the protein to mice that had the mouse equivalent of M.S., their paralysis was reversed. The protein restored order by suppressing the cellular processes causing the damage, explained Ousman. Steinman speculated that the mechanism is tolerization—similar to the process used in allergy shots, when a person with an allergy gets an injection of the protein that is causing problems for the body, so it can learn to ignore it.
Once the researchers had a grasp of what was occurring in mice, they turned to humans.
Using a collection of spinal fluid samples from a collaborator at Harvard Medical School, Steinman’s team tested them on their antibody arrays. The arrays—developed with Stanford colleagues William Robinson, MD, PhD, assistant professor of medicine, and P.J. Utz, MD, associate professor of medicine—are glass slides spotted with minute amounts of hundreds of myelin sheath proteins to provide a profile of the antibodies’ targets.
They found that in humans, too, the highest antibody response was directed against alphaB-crystallin, leading the researchers to speculate that the protein could possibly reverse the damage in humans as it does in mice. “I am going to strenuously work to bring this from our benches to the bedside,” said Steinman, “either through collaborations with existing companies, or we will start a new one.”
This work was funded by the National Institutes of Health, the National Multiple Sclerosis Society and the Multiple Sclerosis Society of Canada. Other Stanford researchers who participated in this work are Beren Tomoka, life research assistant, and Raymond Sobel, MD, professor of pathology.
Acorda Therapeutics Begins Second Phase 3 Clinical Trial of Fampridine-SR in Multiple Sclerosis
HAWTHORNE, N.Y.--(BUSINESS WIRE)--Jun 6, 2007 - Acorda Therapeutics
(Nasdaq: ACOR) announced today that it has begun a second Phase 3
clinical study of Fampridine-SR in multiple sclerosis (MS), with the
randomization of its first patient into the treatment phase of the
study. The study is expected to enroll approximately 200 patients at
35 leading MS clinical centers in the United States and Canada.
Fifteen centers have been initiated and are in the process of
screening subjects for the trial.
The MS-F204 study, which is conducted under a Special Protocol
Assessment (SPA) issued by the Food and Drug Administration (FDA),
will evaluate the safety and efficacy of Fampridine-SR in improving
walking ability in people with MS. An SPA is a process in which the
FDA provides guidance on a Phase 3 clinical trial whose data will
form the primary basis for an efficacy claim. Pending clinical
results from MS-F204, FDA has agreed that this study together with
the previous Phase 3 study would be adequate to support a New Drug
Application (NDA) for Fampridine-SR.
The primary outcome measure for the study will be a walking response
criterion, defined as a consistent improvement in walking speed as
measured by the Timed 25-Foot Walk. The secondary outcome measure for
this study is the Lower Extremity Manual Muscle Test (LEMMT).
Individuals who are interested in learning about study enrollment may
call, 877-617-2494 toll-free, weekdays from 10:00 am to 4:00 pm
"As a clinician I see how impaired walking affects my patient's
ability to conduct even the most routine tasks," said Lauren Krupp,
M.D., Professor of Neurology and Psychology, Stony Brook University.
"A drug that could improve walking ability would be a significant
contribution to the treatment of people with MS."
Ron Cohen, M.D., President and CEO of Acorda Therapeutics, said,
"Walking impairment in MS is pervasive and seriously debilitating in
this patient population. We are proud to be working towards an
important treatment that potentially may help to address this major
unmet medical need."
Multiple sclerosis is a chronic, usually progressive disease of the
central nervous system in which the immune system attacks and
destroys the structure, and therefore degrades the function, of nerve
cells. Approximately 400,000 Americans have MS, and every week about
200 people are newly diagnosed. Most are between the ages of 20 and
50, and women are affected two to three times as much as men.
Worldwide, MS may affect 2.5 million individuals.
According to the National Multiple Sclerosis Society (NMSS), the
direct costs of medical care for MS patients in the United States
exceed $6 billion annually. Additionally, a recent NMSS analysis
estimated the total cost of MS, including medical and non-medical
care, production losses, and informal care, at more than $47,000 per
U.S. patient per year. Complications from MS may make it harder for
people to work and may interfere with their ability to perform
common, daily activities.
For most people with MS, the disease slowly progresses with a series
of unpredictable flare-ups, also called relapses or exacerbations.
But for some, the progression of the disease is rapid. Each relapse
tends to lead to increasing disabilities such as walking impairment,
muscle weakness or speech or vision impairments. Approximately 80
percent of people with MS experience some form of walking disability.
Within 15 years of an MS diagnosis, 50 percent of patients often
require assistance walking and in later stages, about a third of
patients are unable to walk. According to the NARCOMS (North American
Research Committee on Multiple Sclerosis) patient registry,
approximately 80 percent of people with MS experience some degree of
walking impairment. Additionally, mobility issues tend to worsen over
time and seem to be independent of the type of MS diagnosed.
Fampridine-SR is a sustained-release tablet formulation of the
investigational drug fampridine (4-aminopyridine, or 4-AP). Data
collected in laboratory studies found that fampridine can improve the
communication between damaged nerves, which may result in increased
Fampridine-SR Mechanism of Action
A nerve cell has one extension, called an axon, which it uses to
communicate via electrical signals to other nerve cells. All but the
smallest axons have a special covering of a fatty substance called
myelin that acts as insulation to preserve and speed these nerve
signals, much like the insulating cover of an electrical cord helps
preserve the transmission of electricity.
In MS, the myelin becomes damaged and the axon cannot effectively
transmit electrical impulses. Specifically, the damaged myelin
exposes channels in the membrane of the axon, which allow potassium
ions to leak from the axon, dissipating the electrical current.
Fampridine-SR blocks these exposed channels, and helps the electrical
signals to pass through areas of damage.
BIOMS MEDICAL INITIATES ENROLLMENT IN PIVOTAL U.S. PHASE III MULTIPLE SCLEROSIS TRIAL
Edmonton, Alberta, June 5, 2007 - BioMS Medical Corp (TSX: MS), a leading developer of products for the treatment of multiple sclerosis (MS), today announced that the first patients have been enrolled in MAESTRO-03, its U.S. pivotal phase III clinical trial of MBP8298, a proprietary synthetic peptide for the treatment of multiple sclerosis. The randomized, double-blind study is enrolling approximately 510 secondary progressive MS patients at approximately 60 sites across the U.S. who will be administered either MBP8298 or placebo intravenously every six months for a period of two years.
“This is an important milestone in our strategy to commercialize MBP8298 on a global basis,” said Kevin Giese, President and CEO of BioMS Medical. “The U.S. represents nearly half of the MS market and a successful outcome to this trial would put BioMS in a strong position to capture a significant portion of this and other major MS markets.”
The primary clinical endpoint for the MAESTRO-03 trial is defined as a statistically significant time to disease progression as measured by the Expanded Disability Status Scale (EDSS), in patients with HLA-DR2 and/or HLA-DR4 immune response genes. Up to 75% of all MS patients are HLA-DR2 and/or HLA-DR4 positive.
MBP8298 is being assessed in two additional ongoing trials:
• MAESTRO-01 is a pivotal phase III trial being conducted in Canada and Western Europe evaluating MBP8298 for the treatment of secondary progressive multiple sclerosis (SPMS). The trial is a randomized, double-blind study and is fully recruited with 611 patients.
• MINDSET-01 is a phase II trial evaluating MBP8298 for the treatment of relapsing-remitting multiple sclerosis (RRMS). The trial is a randomized, double-blind study and is fully recruited with approximately 215 patients.
Patients who are interested to learn more about these trials should visit: http://www.biomsmedical.com/maestro_03.asp
About MBP8298 - Novel Mechanism of Action
In MS patients, the body's immune system inappropriately attacks the myelin coating around the nerves in the brain and spinal column, whereas healthy people are otherwise “tolerant” of such common body components. The proposed mechanism of action of MBP8298 is, by design, to re-introduce such a state of “tolerance” to a critical portion of the nerve's Myelin Basic Protein that is an immunological site of attack in many MS patients. This is accomplished by the I.V. injection of MBP8298 every six months.
Phase II and long-term follow-up treatment of MS patients with MBP8298, recently published in the European Journal of Neurology showed that MBP8298 safely delayed the median time to disease progression for five years in progressive MS patients with HLA-DR2 or HLA-DR4 immune response genes.
Latest Stem Cell News Dec 7, 2000
December 7, 2000
COLLEGE PARK, Md.--(BW HealthWire)--Dec. 6, 2000 via NewsEdge Corporation -
New Understanding of Stem Cell Behavior Could Have Long-Term Benefit
for Neurological Diseases Such as Parkinson's & Alzheimer's, As Well
as Genomics, and New Drug Research
Taking a significant step forward beyond current scientific
understanding of stem cell behavior and research, a leading
researcher has published major findings that assert that CNS (central
nervous system) stem cells have specific roles and functions, with
certain CNS stem cells developing into the specific neurons needed to
control different brain activities and development.
In a paper entitled "Region-Specific Stem Cells of Mammalian CNS"
published in the most recent issue of NeuroScience News, Dr. Karl
Johe, Co-founder and Chief Scientific Officer of NeuralStem
Biopharmaceuticals, Ltd. provides conclusive evidence that the
cellular diversity of the brain is generated not from one type of
all-purpose stem cell, but from many different types of
"multipotential" CNS stem cells, each differentiating into specific
types of neurons that perform different functions.
"We find that there are many distinct populations of neural stem
cells, which are distinguishable functionally by the neuronal
phenotypes that arise from each population," the study's abstract
states. Some recent studies have suggested that stem cells have no
distinct character, but rather can be turned into any type of brain
Dr. Johe has, for the first time ever, been able to isolate and
identify the functions of stem cells derived from human neurons in
culture. "The results of our research demonstrate conclusively that
CNS stem cells are not blank cells but contain quite stable and
complex information and have the ability to differentiate into many
different types of neurons," stated Dr. Johe.
According to Johe, the research findings lead to at least one
important immediately practical implication for applying CNS stem
cells in cell therapy - - in order to repair a particular region of
the adult CNS, stem cells isolated from a corresponding fetal region
will have the best chance of differentiating and integrating into an
adult host brain.
In addition, because the CNS stem cells can now be differentiated and
reproduced in large quantities in culture, they can be considered an
ideal renewable source of transplantable cells for neural repair. CNS
stem cells can also be cryopreserved in a serum-free medium and
recovered after long-term storage with 85-90% efficiency.
Transplantation studies at NeuralStem are currently in progress with
human NeuralStem- patented CNS stem cells to quantify their ability
to survive and differentiate into the correct neuronal phenotypes as
predicted by their in-vitro behavior.
NeuralStem Biopharmaceuticals, Ltd. is a privately held company
developing a proprietary, patented central nervous system (CNS) stem
cell technology platform to provide powerful new therapeutics and
research tools for drug discovery. From genomics to cellular
therapeutics, NeuralStem is developing a new generation of
biotherapeutic products to treat and cure neurodegenerative and
neurological disorders of the brain and spinal cord, such as
Parkinson's disease, Alzheimer's disease, stroke, multiple sclerosis,
spinal cord injury and epilepsy.
CONTACT: NeuralStem Biopharmaceuticals, Ltd. | Richard Garr,
301/571-9323 | or | The Hawthorn Group | Patricia Limoges,
Article Found In Biomaterials Central Nervous System Disorders
Central Nervous System Drugs Transplantation Cellular Therapy Quick
Copyright © 2000, Individual.com, Inc.TM
FDA approves Novantrone for Worsening Forms of Multiple Sclerosis SEATTLE, Oct. 13 /PRNewswire
SEATTLE, Oct. 13 /PRNewswire/ -- Immunex Corporation (Nasdaq: IMNX) today announced the
approval by the U.S. Food and Drug Administration (FDA) of NOVANTRONE(R) (mitoxantrone
for injection concentrate) as the first therapy approved for secondary progressive multiple
sclerosis (MS). NOVANTRONE is now indicated for reducing neurologic disability and/or the
frequency of clinical relapses in patients with secondary progressive, progressive relapsing or
worsening relapsing-remitting MS.
"The approval of NOVANTRONE offers a new treatment option for people with
secondary-progressive, progressive-relapsing MS, and worsening relapsing-remitting MS," said
Dr. Stephen Reingold, vice president for research at the National Multiple Sclerosis Society.
Immunex filed for expanded labeling for NOVANTRONE for the treatment of patients with
worsening MS on June 7, 1999, and was unanimously recommended for approval on January 28,
2000, by the FDA Peripheral and Central Nervous System Drugs Advisory Panel.
The new MS indication is based on results from a 24-month Phase III clinical trial in which
NOVANTRONE, at a dose of 12 mg/m2, was administered by short IV infusion once every three
months. This trial demonstrated that NOVANTRONE had a statistically significant impact on
prolonging time to first treated relapse and on delaying disability progression in patients with
secondary progressive or progressive relapsing MS. There was also a significant reduction in the
mean number of treated relapses. There was a significant reduction in the number of
NOVANTRONE patients who had new MS lesions seen on magnetic resonance imaging (MRI).
"The approval of NOVANTRONE offers new hope for people who otherwise would not have an
approved treatment," said Donald Goodkin, M.D., Immunex senior clinical scientist.
"NOVANTRONE is to me just another word for hope," said Debbie Salazar, NOVANTRONE
patient. "I think it's wonderful that it's available."
The most common side effects of NOVANTRONE in patients with MS in clinical trials have been
nausea, hair loss, bladder infections, changes in menstrual cycle, mouth sores, diarrhea,
constipation, and changes in cardiac rhythm. NOVANTRONE should not be used by people with
serious heart problems, liver disease or certain blood disorders.
Patients treated with NOVANTRONE may develop serious heart problems. To measure potential
changes to the heart, people taking NOVANTRONE should have regular testing of their heart's
ability to pump blood. Because of risk of injury to the heart, there is a limit on the total lifetime
amount of NOVANTRONE a person can receive. For most patients this is approximately 8 to 12
doses over 2 to 3 years. Patients and their doctors should carefully keep track of how much
NOVANTRONE is administered.
NOVANTRONE can increase potential for infection. Prior to each dose of NOVANTRONE, blood
samples should be taken to check blood counts and liver function. Women who are pregnant,
trying to become pregnant, or breastfeeding should not use NOVANTRONE. Also, it is
recommended that women who are biologically capable of becoming pregnant, even if they are
using birth control, should have a pregnancy test prior to each dose.
Multiple sclerosis is a chronic, often debilitating disease of the central nervous system that, in
its various stages, affects over one third of a million people in the United States. The symptoms
of MS result when a breakdown occurs in the myelin sheath, the fatty substance that insulates
the nerve fibers of the brain and spinal cord. This demyelination process causes patches of scar
tissue, or "sclerosis," which interfere with the nerve's ability to transport messages from the
brain to body parts. This can result in a variety of symptoms that range from numbness in the
limbs, to complete paralysis.
Approximately half the 350,000 U.S. patients with MS will eventually develop active progressive
forms of the disease, known as secondary progressive, progressive remitting and worsening
relapsing-remitting MS. These conditions are characterized by:
a progression of disability that significantly impacts functioning; or
patients who are diagnosed with relapsing-remitting disease, in which their symptoms
flare up and then ease or even disappear for months or years; or
patients who are diagnosed with secondary progressive MS, in which their symptoms
steadily worsen, as flares become more frequent and severe, and recovery is incomplete.
For more information about MS, contact The National Multiple Sclerosis Society, at
800-Fight-MS (800-344-4867), visit their web site at www.nmss.org, or visit
www.msknowledge.com, an informational site sponsored by Immunex.
NOVANTRONE acts in people with MS by suppressing the activity of certain white blood cells
known as T cells, B cells and macrophages that are thought to lead the attack on the myelin
sheath. It is currently marketed, in combination with corticosteroids, to treat pain in patients
with advanced hormone-refractory prostate cancer and for initial therapy of acute
nonlymphocytic leukemia. Full prescribing information for NOVANTRONE can be obtained by
calling 800-5-NOVANTRONE (800-566-8268) or by visiting www.novantrone.com or
Immunex Corporation is a leading biopharmaceutical company dedicated to improving lives
through immune system science innovations.
American Home Products Corporation owns a majority interest in Immunex. AHP is one of the
world's largest research-based pharmaceutical and health care products companies. It is a
leader in the discovery, development, manufacturing and marketing of prescription drugs,
including biotechnological and vaccine products, animal health care products and
This news release contains forward-looking statements that involve risks and uncertainties,
including risks associated with clinical development, regulatory approvals, our reliance on
third-party manufacturers, product commercialization and other risks described from time to
time in the SEC reports filed by Immunex, including the most recently filed Form 10-Q. An
electronic version of this news release -- as well as additional information about Immunex of
interest to investors, customers, future employees and patients -- is available on the Immunex
home page at www.immunex.com.
SOURCE Immunex Corporation
CONTACT: media, Tim Warner, 206-470-4193, or investors, Mark Leahy, 206-389-4363, both for
Immunex Corporation (Immunex has been changed to Amgen, Both JoAnne and Sounder of
CLAMS have undergone Novntrone treatment
Angiotech's micellar paclitaxel
The following article has been approved by The Doctor's Guide to
Paclitaxel Shows Benefits In Secondary Progressive MS
VANCOUVER, B.C. -- October 15, 1999 -- Patients with secondary
progressive multiple sclerosis (SPMS) treated with monthly
intravenous infusions of Angiotech's micellar paclitaxel showed
favourable trends in Expanded Disability Status Scale (EDSS) score,
MS functional scores, quality of life and magnetic resonance imaging
(MRI) burden of disease.
Dr. Paul O'Connor, of St. Michael's Hospital, in Toronto, ON,
presented these findings of a phase I/II study were reported earlier
this week at the American Neurological Association's (ANA) 124th
Annual Meeting in Seattle, WA.
A total of 29 patients with EDSS scores ranging between 3.5 (some
neurological disability) and 6.5 (unable to walk without a walker or
two canes) were treated monthly with 25 or 50 mg/m2 of
micellar paclitaxel for a total of six months.
No drug-related serious adverse reactions were observed. When
compared to baseline, favourable trends were observed in EDSS
(improvements of 0.35 for the low-dose group and 0.27 for the
high-dose group) and in the proportion of patients showing
stabilization or improvement of their condition (80 percent and 85
When the study results were compared to a historical placebo group
(63 SPMS placebo-treated subjects from the North American
Trial which closely matched the two micellar paclitaxel-treatment
groups for clinical and MRI parameters at baseline), the change in
EDSS from baseline statistically favoured the micellar
paclitaxel-treated patients (i.e., placebo-treated patients worsened
by 0.27, while micellar paclitaxel-treated patients improved by 0.27
In functional testing, a statistically significant proportion of
patients in both dosing groups (p=0.02 and 0.03, low and high dose
respectively) showed improvement in the 9-hole peg test (the time
takes to put 9 pegs into a pegboard). In the Paced Auditory Serial
Addition Test (the time taken to add up a series of numbers), again
it was found that in both micellar paclitaxel groups a statistically
significant proportion of patients improved compared to baseline
(p=0.02 and 0.001, low and high dose respectively). For the timed
25-foot walk, only the high dose group demonstrated a statistically
significant improvement over the six month investigation (p=0.27
p=0.03, low and high dose respectively).
Patients were also evaluated by MRI (computer-assisted analysis of
AFFIRMATIVE and T1 images) before the initiation of, and after the
completion of, treatment. Positive trends were seen for changes in
the MRI burden of disease that favoured the patients treated with
mg/m2 micellar paclitaxel. The median percent increase in burden of
disease was as follows: 6.7 percent for historical controls, 6.23
percent for low dose, and 1.2 percent for high dose; suggesting
micellar paclitaxel treatment slowed disease progression in the
higher dose range. In conclusion, micellar paclitaxel treatment was
very well-tolerated and demonstrated favourable improvement
both clinical and MRI parameters of SPMS.
Based on these impressive results (and at the patients' and
investigator's requests), Angiotech has continued to treat a majority
of these patients for ethical and compassionate purposes for an
additional six months.
Later this year, Angiotech plans to initiate a 190-patient,
double-blinded, placebo-controlled, phase II MS study at multiple
centers across Canada.
Multiple sclerosis is a chronic inflammatory and progressive disease,
with debilitating neurological symptoms occurring over a period of
several years. Although the disease does not result in early death,
it disables patients by disturbing vision, strength, balance and
sensation, as well as causing fatigue and cognitive problems.
Secondary progressive MS is comprised of 40 percent of all MS
patients. It is the most severe form of MS, which follows the
relapsing-remitting phase of the disease.
All contents Copyright (c) 1999 P\S\L Consulting Group Inc. All
Blood Swap Helps Severe MS
By Jackie Judd -- ABCNEWS.com
Sept. 17 — Multiple sclerosis and central nervous disorders
can lead to paralysis, slurred speech and vision problems.
While there’s no cure, researchers at the Mayo Clinic have
developed a treatment that may help people with the most
A handful of people, like MS patient Andrew Grant, have
already seen the benefits of the new treatment. Though he
was completely immobile two years ago, Grant is up and
moving again thanks to an experimental approach called
He and 18 other patients with severely damaged nervous
systems had blood removed. A special machine then
separated the cells from the plasma, or liquid part of the
blood. Plasma from healthy donors was purified until it
contained just a single protein called albumin. The donor
plasma and the original cells were mixed together and put
back into the patients.
This exchange was repeated seven times over a two-week
‘Big Smile on My Face’
For this group of severely disabled patients, standard
anti-inflammatory treatment hadn’t helped. But plasma
exchange allowed many of them to regain their speech, as
well as movement in their arms and legs.
“We had a robust, major effect in 40 percent of the
patients,” says Dr. Brian Weinshenker, a Mayo Clinic
neurologist and the study’s lead researcher.
In those who were helped, the effect was almost
On Day 14, Grant could get out of bed and walk with
assistance. Six months later, he could walk on his own.
When he felt his foot move, he says, “I put a big old smile on
Doctors are not entirely sure why this treatment
succeeded. An early theory is the patients’ plasma contained
harmful antibodies that allowed the disease to progress at a
rapid pace. The replacement plasma stopped that process.
Not for Everybody
“I think it’s just dramatic,” says Weinshenker, “how touching
the plasma alone, without doing anything to the cells, can
affect an immediate recovery from a neurological disability.”
He and his colleagues presented the results of their study,
which was funded by the National Institutes of Health, at a
medical conference today in Basel, Switzerland. They’ll
publish their findings in the December issue of Annals of
The researchers are careful to point out, however, that the
new treatment isn’t for everyone with MS, and it’s not a cure.
“Plasma exchange should be considered only for those
patients who have severe, acute attacks of MS that are not
responsive to high-dose steroid treatments,” Weinshenker
INTERESTING NEWS REGARDING MRI AND COPAXONE(R)
TORONTO, April 21 /PRNewswire/ via NewsEdge Corporation -- A study presented today at the American Academy of Neurology
annual meeting shows increasing evidence that doctors can use
Magnetic Resonance Imaging (MRI) not only to diagnose multiple
sclerosis, but also to help predict the disease course.
The multi-center trial conducted in Europe and Canada measured
the effect of COPAXONE(R) (glatiramer acetate for injection) on
patients with relapsing-remitting multiple sclerosis. Jerry S. Wolinsky,
M.D., director of the Multiple Sclerosis Research Group at The
University of Texas-Houston Health Science Center, consulted on
the study, and he sees many parallels between this study and
clinical studies conducted at The University of Texas.
"The data collected proves a direct correlation between what we
were finding scientifically and clinically. For patients, these findings
are significant," Dr. Wolinsky said. "The MRI scans can help us look
into the patient's brain and help predict what physical symptoms we
will see in the future. This will help us select and evaluate drug
therapies for patients. "
"Now when patients score well on the Expanded Disability Status
Scale and tell their doctor they are feeling better, we can confirm
why they are feeling better. The reduction in MRI-measured activity
allows us to substantiate our clinical findings," says Dr. Wolinsky.
Expanded Disability Status Scale (EDSS) is a standard clinical rating
scale that measures disability based on the level of neurologic
impairment. The EDSS and MRI are two primary tools used to
diagnose and monitor MS.
MRI technology has made rapid advancements in the last 10 years.
The huge machines have become increasingly sophisticated at
projecting "signals " into a computer that translates that information
into visual images of the brain. The patient lies in the MRI scanner,
which is a cylindrical tube that holds the large and strong magnet.
The machine generates a high magnetic field around the patient's
brain and then bombards the field with radio waves. Variances or
changes in the magnetic field are sent back to the machine.
Technicians work with computers that capture the returning signals
and they are converted into images on a computer screen. The
result is a series of pictures that allow doctors to see what is
happening inside the brain without surgery.
"MRI has revolutionized the diagnosis of multiple sclerosis," said
Ponnada A. Narayana, Ph.D., professor of radiology at The University
of Texas-Houston Health Science Center. "We use MRIs to measure
the number and volume of lesions on the brain. These lesions can
indicate nerve damage and loss, which can cause patients
For multiple sclerosis patients like Bill Krukiel of Houston, this
knowledge is critical when choosing a treatment. Krukiel was
diagnosed with the disease four years ago. Although he experiences
few physical symptoms, he and his doctor are able to tell from his
MRIs that the disease is slowly progressing.
"MRI scans are extremely important to multiple sclerosis patients
because they help them to understand how the disease has
progressed, how the symptoms have progressed. And, it helps them
to make an informative and smart decision about how they are going
to treat the disease," says Krukiel.
The multi-center study studied the effect of COPAXONE(R) on
disease activity, as measured by cerebral MRI in patients with
relapsing-remitting multiple sclerosis. The study took place in Europe
and Canada and followed 239 patients. The first 36 weeks were
placebo controlled and double blinded. Then patients were rolled
over to an open label treatment for an additional 36 weeks.
The investigators found that patients receiving COPAXONE(R)
showed a statistically significant reduction in the volume and number
of new lesions compared to patients in the placebo group. Also,
patients receiving COPAXONE(R) showed a statistically significant
reduction in the relapse rate.
"Multiple sclerosis is an unpredictable disease. Now through the use
of newer technology we may be able to predict the disease better
and assess drug treatments better," says Dr. Wolinsky.
SOURCE University of Texas-Houston Health Science Center
/CONTACT: Sandra Henry of the University of Texas-Houston Health
Science Center, 713-500-3308, or Kara Hendon of Fleishman-Hillard,
Eliprodil stimulates CNS myelination
New prospects for multiple sclerosis?
Corinne Demerens, PhD; Bruno Stankoff, MD; Bernard Zalc, MD, PhD;
Lubetzki, MD, PhD
From the Biologie des Interactions Neurones/Glie (Drs. Demerens,
Stankoff, Zalc, and
Lubetzki), INSERM U-495, Université Pierre et Marie Curie, and the
Neurologie (Drs. Stankoff and Lubetzki), Hopital de la Salpetrière,
C.D. was supported by an Association de Recherche sur la Sclérose
en Plaques fellowship
and B.S. is a fellow from INSERM (poste d’accueil). This study was
supported by INSERM,
Association de Recherche sur la Sclérose en Plaques (C.L.),
Contract BMH4-CT96-0249 (B.Z.), and Synthelabo Recherche.
C.D. and B.S. have contributed equally to this work.
Received May 11, 1998. Accepted in final form October 10, 1998.
Address correspondence and reprint requests to Dr. Catherine
Lubetzki, Biologie des
Interactions Neurones/Glie, INSERM U-495, Hopital de la Salpetrière,
75651, Paris Cedex
Article abstract—Objective: To examine the potential of eliprodil—a
with a high affinity for -receptors—to promote myelination in
cocultures. Background: Remyelination is one of the major
therapeutic issues in MS.
Because neuronal integrity is required for CNS myelination, the
authors postulated that
neuroprotective molecules might favor myelination. Methods: Two
conditions were compared: standard medium Bottenstein and Sato
([B-S] medium) and a
medium depleted of both thyroid hormones and progesterone
(depleted [D] medium).
Myelination was quantified by counting the number of myelinated
immunocytochemically with an antimyelin basic protein (anti-MBP)
antibody. Results: The
authors first confirmed that in D medium myelination was reduced by
a factor of 3.5
compared with cultures maintained in B-S medium. Under both
culture conditions, addition
of 10\-6 M eliprodil did not modify significantly the total number of
associated protein-2-positive neurons or MBP-positive
oligodendrocytes. However, eliprodil
induced a twofold (p < 0.01) increase in myelination when added to
B-S medium, and a
4.7-fold (p < 0.0001) increase when added to D medium.
Conclusions: Although the
molecular mechanism mediating the effect of the -receptor agonist
on myelination remains
to be elucidated, these results strongly suggest that
neuroprotective molecules may be of
therapeutic interest in demyelinating diseases such as MS.
NEUROLOGY 52 January (2 of 2) 1999
Copyright © 1999 by the American Academy of Neurology. All rights
Published by Lippincott Williams & Wilkins
From Irwin Mortman
Researchers Identify Molecules Involved in MS Inflammation
The following article has been approved by PRNewswire
Researchers Identify Molecules Involved in MS Inflammation
Study raises hopes that MS could be treated by blocking chemokine receptors
CLEVELAND, March 8 /PRNewswire/ -- An international team of
researchers have identified some of the molecules that lead to
inflammation of the brain among multiple sclerosis patients,
according to a study published in this month's issue of "The Journal
of Clinical Investigation." The finding suggests that MS could be
treated by blocking the cell receptors for those molecules, similar
to treatments currently being developed for diseases as diverse as
asthma and AIDS. "Multiple sclerosis is a disease in which white
blood cells invade the brain and the resulting inflammation injures
the central nervous system. To stop this inflammation, we need a
better understanding of the molecular details behind this process,"
said the study's lead author, Richard M. Ransohoff, M.D., a
neuroscientist at the Cleveland Clinic's Lerner Research Institute
and the Mellen Center for Multiple Sclerosis Treatment and Research.
Researchers from the Lerner Research Institute, the University of
Copenhagen in Denmark, the Mayo Clinic and the University of Michigan
Medical Center studied molecules called chemokines, which attract the
white blood cells. They identified two chemokines and two receptors
that appear to be associated with the active disease in MS patients.
The chemokines are produced by cells in the central nervous system.
The receptors are found on white blood cells that are attracted to
the chemokines and travel in the blood to the origin of chemokine
production. The clustering of white blood cells at the source of
specific chemokine production is a critical factor in inflammation of
the nervous system. "These chemokines are like honey to the bee. The
chemokines are secreted from cells and get caught up in the matter
surrounding the nervous system cells. Certain white blood cells seek
out the chemokines. These cells include the orchestrators of
inflammation, activated T-cells, and macrophages, their major
henchmen in the inflammation of MS. White blood cell chemokine
receptors bind to the chemokines, and the cells then take up
residence at sites of inflammation in the nervous system," said Dr.
Ransohoff. "While these white blood cells are normally an important
part of our immune system, they become destructive in people with
MS." Researchers have studied the role of chemokines in other
diseases, such as rheumatoid arthritis and asthma, but this was the
first in-depth study examining their role in MS. Now that the
individual chemokines and receptors have been identified, Dr.
Ransohoff said, the next step is to develop molecules that block
receptors on white blood cells so that those cells fail to migrate to
the nervous system source of chemokines. Since recent studies have
documented a direct correlation between inflammation in the central
nervous system and the progression of MS, blocking these cells could
have a profound impact on the disease, said Dr. Ransohoff. Receptor
blocking research is currently underway for other diseases, such as
AIDS. MS researchers could build on that work to develop a treatment
for MS, Dr. Ransohoff said. "With many diseases, we can treat only
the symptoms. To truly stop these diseases, we must combat them on
the molecular level," said Dr. Ransohoff. "This study lays the
foundation for a new generation of treatments for multiple
sclerosis." About 350,000 Americans have been diagnosed with multiple
sclerosis. It can strike at almost any age but is most common among
people in their 20s and 30s. In fact, it is the leading cause of
nontraumatic neurological disability among young adults in North
America. Women are almost twice as likely to be diagnosed with MS
than men. The Cleveland Clinic, through the Department of
Neurosciences and the Mellen Center for Multiple Sclerosis, maintains
one of the country's largest programs for the MS treatment and
research. The Cleveland Clinic's website address is: http://www.ccf.org
From Irwin Mortman
First Novantrone Phase III Results in Multiple Sclerosis 09:19 a.m. Sep 10,
STOCKHOLM, Sweden, Sept. 10 /PRNewswire/ -- Researchers at the 14th
Congress of the European Committee for Treatment and Research in Multiple
Sclerosis (ECTRIMS) reported today that in preliminary results of a Phase
III clinical trial, Novantrone(R) (mitoxantrone for injection concentrate)
had a statistically significant impact on relapse rate and disability
progression in patients with progressive multiple sclerosis (MS). Magnetic
resonance imaging (MRI) data were also reported that corroborated the
Novantrone was administered by short, IV infusion once every three months
in this trial. Other treatments currently approved for MS require a
subcutaneous or intramuscular self-injection on a daily or weekly basis.
"While current therapies have provided a major step forward for the
treatment of multiple sclerosis, there is still a need for new therapy
options for people with the disease," said Jeanne Oates Angulo, President
of the National Capital Chapter of the National Multiple Sclerosis Society.
"We look forward to learning more about Novantrone and the scientific
communities evaluation of these clinical results."
Multiple sclerosis is a highly debilitating illness that afflicts more than
300,000 Americans and more than one million people worldwide. This
autoimmune disease attacks the central nervous system. The nerve fibers of
the brain and spinal cord are insulated by a fatty substance called myelin,
which helps conduct the flow of nerve impulses to and from the brain. But
in people with MS, myelin is damaged, causing scar tissue, or sclerosis,
that can distort or even block messages from the brain. This can result in
a variety of symptoms that range from numbness in the limbs to complete
Novantrone is currently marketed to treat pain in patients with advanced
hormone-refractory prostate cancer in combination with corticosteroids and
for initial therapy of acute nonlymphocytic leukemia. It is not approved
for use in MS patients.
"We are encouraged by the results with Novantrone reported in this study,"
said Peggy Phillips, senior vice president, pharmaceutical development,
Immunex Corporation (Nasdaq: IMNX). "We are looking forward to meeting with
the Food and Drug Administration to discuss applying for an expanded label
for the use of Novantrone in MS."
The Phase III, multicenter, placebo-controlled, randomized, observer-blind
trial in 194 patients with progressive MS assessed the effects of
Novantrone on disease progression. The study investigators compared two
doses of Novantrone -- 12 mg/m2 and 5 mg/m2 -- with placebo, and
administered each treatment intravenously once every three months for two
There was a statistically significant difference in the duration of time
from initiation of treatment to the first severe MS attack, defined as the
occurrence of a new symptom or the worsening of an existing symptom that
requires treatment with corticosteroids, the most commonly used medication
for controlling such episodes. The median time to first relapse was not
reached after 24 months for both of the Novantrone doses and was 15 months
for the placebo group.
The difference in annual relapse rates was also significant, with a rate of
21 in the Novantrone 12 mg/m2 dose group compared to 60 for placebo. The
relapse rate was 36 for the 5 mg/m2 dose. The percentage of patients who
had confirmed treatment failure was 7 for the 12 mg/m2 dosage, 9 for the 5
mg/m2 dosage, and 19 for placebo.
The study investigators also used MRI in a subgroup of 110 patients at 12
and 24 months. The MRIs detected almost no additional lesions (scar
tissue), an objective indicator of disease progression, in either the 5 or
12 mg/m2 Novantrone groups. In the placebo group, however, the MRI found a
continuous increase in lesions at 12 and 24 months. There was a significant
decrease in gadolinium-enhanced lesions in the 12mg/m2 group as compared to
the placebo group.
Investigators also reported that patients receiving Novantrone had an
improvement of their neurologic function as measured by the Expanded
Disability Status Scale (EDSS), the standard clinical rating scale used to
evaluate disability progression in MS clinical trials. The EDSS measures
disability based on the level of neurologic impairment. The EDSS rates a
patient's level of function from zero (normal neurological exam) to 10
(death due to MS), with every half-point increase on the scale representing
a progressive deterioration of ability. Mean change from baseline in EDSS
score was -0.13 for patients receiving the 12 mg/m2 dose and -0.23 for the
5 mg/m2 dose compared to +0.23 for placebo.
In addition, patients who received Novantrone had less deterioration of
their mobility based on scores from the Ambulatory Index (AI), another
measure of patient symptoms and disease progression. The AI rates a
patient's mobility from zero (asymptomatic or fully active) to nine
(restricted to wheelchair and unable to transfer independently). The mean
change in score for Novantrone doses was +0.30 for the 12 mg/m2 dose and
+0.41 for the 5 mg/m2 dose compared to +0.77 for placebo.
Overall, treatment with Novantrone resulted in generally manageable side
effects in this trial. The most frequently reported side effects were
neutropenia (a reduced number of white blood cells), infection and alopecia
(hair loss), which occurred in 11, 10 and 5 percent of the patients
Novantrone has been studied in MS preclinically and clinically for over a
decade. The results of this Phase III study are consistent with the
outcomes from these earlier trials. In several experiments of a model of
MS, Novantrone showed prevention of disease relapse and progression in
mice. These preclinical studies led to the start of investigations in
several countries of Novantrone in patients with MS. Several Phase I and II
trials were conducted that showed a reduction in new lesions on MRI, as
well as reductions in the number and severity of relapses in
Immunex holds the marketing rights for Novantrone in North America.
Wyeth-Ayerst International, which is a division of American Home Products,
markets Novantrone outside North America.
Immunex Corporation is a biopharmaceutical company dedicated to developing
immune system science to protect human health. The company's products offer
hope to patients with cancer, inflammatory and infectious diseases.
American Home Products Corporation owns a majority interest in Immunex.
AHPC is one of the world's largest research-based pharmaceutical and health
care products companies and is a leading developer, manufacturer and
marketer of prescription drugs and over-the-counter medications. It is also
a leader in vaccines, biotechnology, agricultural products and animal
For full prescribing information for Novantrone, please call Lisa Crisera,
206-389-4346. For assistance determining insurance coverage, please call
the Immunex Reimbursement Hotline 800-321-4669.
NOTE: This news release contains forward-looking statements that involve
risks and uncertainties, including risks associated with clinical
development, regulatory approvals, product commercialization and other
risks described from time to time in the SEC reports filed by Immunex,
including the most recently filed Form 10-Q.
An electronic version of this news release -- as well as additional
information about Immunex of interest to investors, customers, future
employees and patients -- is available on the Immunex web site at
www.immunex.com. SOURCE Immunex Corporation