| February 27, 2015 Mount Sinai Medical Center A newly characterized group of pharmacological compounds block both the inflammation and nerve cell damage seen in mouse models of multiple sclerosis, according to a study. Multiple sclerosis is a disease of the brain and spinal cord, where for unknown reasons, the body's immune system begins an inflammatory attack against myelin, the protective nerve coating that surrounds nerve fibers. Once myelin is stripped from these fibers, the nerve cells become highly susceptible to damage, which is believed to underlie their destruction, leading to the steady clinical decline seen in progressive forms of multiple sclerosis. A newly characterized group of pharmacological compounds block both the inflammation and nerve cell damage seen in mouse models of multiple sclerosis, according to a study conducted at the Icahn School of Medicine at Mount Sinai and published online this week in the journal Nature Neuroscience. Multiple sclerosis is a disease of the brain and spinal cord, where for unknown reasons, the body's immune system begins an inflammatory attack against myelin, the protective nerve coating that surrounds nerve fibers. Once myelin is stripped from these fibers, the nerve cells become highly susceptible to damage, which is believed to underlie their destruction, leading to the steady clinical decline seen in progressive forms of multiple sclerosis. "The compounds identified in this study, when administered orally, both reduced the inflammation that is a hallmark of multiple sclerosis and protected against the nerve cell damage seen in mouse models of the disease," said Jeffery Haines, PhD, a post-doctoral fellow at Mount Sinai and the study's lead author. "The multiple sclerosis drugs currently on the market and being tested elsewhere seek to reduce the immune attack on cells, but none target neurodegeneration nor do they work to restore nerve cell function. The findings of this new study represent an exciting step in the process of advancing new oral treatment options." Previous research conducted at Mount Sinai found that the trafficking of protein molecules between the nucleus (the cellular compartment containing the genetic information of the cell) and the cytoplasm is altered in neurodegenerative disease. The molecule that shuttles proteins between the nucleus and cytoplasm, XPO1 (also called CRM1,) has been implicated in multiple sclerosis and a number of other diseases. Specifically, the Mount Sinai study was designed to test whether pharmacological compounds designed to block the function of XPO1/CRM1 could stop disease progression in mouse models that exhibit some of the characteristics of MS. Researchers found that two chemical agents (called KPT-276 and KPT-350) prevented XPO1/CRM1 from shuttling cargo out of the nucleus of nerve cells, which protected them from free radicals and structural damage. The compounds also stopped inflammatory cells from multiplying, thereby reducing inflammation. Mice showing hindlimb paralysis were able to regain motor function within two weeks after KPT-276 or KPT-350 were orally administered. "The study results elucidate the molecular mechanisms underlying disease progression in multiple sclerosis models, providing a basis for future clinical trials to determine safety and efficacy of these chemical agents in humans with demyelinating disorders," says Patrizia Casaccia, MD, PhD, Professor of Neuroscience, Genetics and Genomic Sciences at Mount Sinai and senior author of the study. Because traffic of molecules between the nucleus and the cytoplasm of nerve cells is altered in several other neurodegenerative disorders, targeting nuclear transport may have broader therapeutic implications in diseases like amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. Story Source: The above story is based on materials provided by Mount Sinai Medical Center. Note: Materials may be edited for content and length. Journal Reference:
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domingo, 1 de março de 2015
New compounds protect nervous system from the structural damage characteristic of multiple sclerosis
terça-feira, 2 de dezembro de 2014
New hope for MS sufferers: Drug shown to alleviate symptoms in mice
| Seema Tiwari-Woodruff, associate professor of biomedical sciences at the UC Riverside School of Medicine (Photo: I. Pittalwala, UC Riverside)
Researchers are zeroing in on what looks like an effective treatment for the symptoms of Multiple Sclerosis. Teams from UC Riverside and New York's Rockefeller University have both used the same compound, indazole chloride, to successfully reverse the progression of MS in mice. The drug appears to be able to stimulate the regeneration of the myelin sheath – the nerve pathway coating that is progressively destroyed as MS attacks the nervous system. MS affects around 400,000 people in the United States alone, and some 2.5 million around the world, according to Healthline. It's a debilitating disease in which the body's immune system begins to attack its own nervous system, gradually breaking down the protective cover called the myelin sheath, which coats the axons of nerve fibers in the brain and spinal cord. As this demyelination progresses, patients begin to slowly experience the breakdown of their nervous system – sensation, vision and motor control begin to slowly degenerate, and permanent paralysis can be the end result. It's a horrible sentence. One well known quirk of the disease is that female sufferers seem to have a reversal of their MS symptoms during the third trimester of pregnancy. This reversal has them feeling great for a couple of months, but then the symptoms reappear with a vengeance after childbirth. This led researchers to investigate pregnancy hormones. They found that estriol, a form of estrogen, had a significant effect reducing the MS symptoms of lab mice. But estrogen is a highly compromised treatment. It's been strongly linked to breast and uterine cancers, and has a feminizing effect which makes it particularly unattractive to male sufferers. Which led researchers from UC Riverside and Rockefeller University to start investigating compounds that might produce a similar effect on MS symptoms without the hormonal side effects. Both teams have zeroed in on indazole chloride, a ligand that stimulates the ERβ estrogen receptors in the body without requiring raised levels of estrogen. And both teams have reported impressive results reversing the progression of MS symptoms in mice. The drug appears to be effective long after the onset of the disease, and seems to be able to stimulate the rebuilding of the myelin sheath, not only in MS cases, but in cases of traumatic brain and spinal cord injury. In simple terms, if the nerves haven't already been totally destroyed, indazole chloride helps rebuild them. "Our work on mice suggests that its effect is permanent," said Associate Professor Seema K. Tiwari-Woodruff of UC Riverside. "But perhaps more significant, Ind-Cl remyelinates, that is, it makes new sheaths around those axons that have not been lost for good. This means Ind-Cl not only inhibits inflammation but is capable of reducing axon degeneration and restoring neuronal function… Ind-Cl works in two ways: through the immune system in terms of reducing brain and spinal cord inflammation, and directly by remyelinating the axons. This makes it an extremely promising drug." We've written before about promising potential MS cures, particularly Dr. Zamboni's CCSVI work, but that proved to be completely ineffective under rigorous scientific testing. In contrast, the Riverside team expects to go to clinical trial soon. The teams believe the drug can be tweaked to be even more effective, and eventually administered orally. So, it's promising news for MS sufferers and their families, but there's still an agonizing wait ahead. Source: UC Riverside and Rockefeller University (PNAS)
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quarta-feira, 8 de outubro de 2014
Could Multiple Sclerosis Begin in the Gut?
MS researchers are focusing on the content of the gut’s microbiome as a possible contributor to the body’s autoimmune attack on its nervous system
Oct 8, 2014 By Bret Stetka
Mounting evidence suggests that when our resident biota are out of balance, they contribute to numerous diseases, including diabetes, rheumatoid arthritis, autism and, it appears, MS. Credit: ARS via Wikimedia Commons
Multiple sclerosis (MS) is an electrical disorder, or rather one of impaired myelin, a fatty, insulating substance that better allows electric current to bolt down our neurons and release the neurotransmitters that help run our bodies and brains. Researchers have speculated for some time that the myelin degradation seen in MS is due, at least in part, to autoimmune activity against the nervous system. Recent work presented at the MS Boston 2014 Meeting suggests that this aberrant immune response begins in the gut.
Eighty percent of the human immune system resides in the gastrointestinal tract. Alongside it are the trillions of symbiotic bacteria, fungi and other single-celled organisms that make up our guts’ microbiomes. Normally everyone wins: The microorganisms benefit from a home and a steady food supply; we enjoy the essential assistance they provide in various metabolic and digestive functions. Our microbiomes also help calibrate our immune systems, so our bodies recognize which co-inhabitants should be there and which should not. Yet mounting evidence suggests that when our resident biota are out of balance, they contribute to numerous diseases, including diabetes, rheumatoid arthritis, autism and, it appears, MS by inciting rogue immune activity that can spread throughout the body and brain.
One study presented at the conference, out of Brigham and Women’s Hospital (BWH), reported a single-celled organism called methanobrevibacteriaceae that activates the immune system is enriched in the gastrointestinal tracts of MS patients whereas bacteria that suppress immune activity are depleted. Other work, which resulted from a collaboration among 10 academic researcher centers across the U.S. and Canada, reported significantly altered gut flora in pediatric MS patients while a group of Japanese researchers found that yeast consumption reduced the chances of mice developing an MS-like disease by altering gut flora.
Sushrut Jangi, a staff physician at Beth Israel Deaconess Medical Center in Boston who co-authored the BWH study, thinks that regional dietary influences might even be at play. “The biomes of people living in different areas and who consume Western versus non-Western diets are demonstratively different,” he says. “People who emigrate from non-Western countries, including India, where MS rates are low, consequently develop a high risk of disease in the U.S. One idea to explain this is that the biome may shift from an Indian biome to an American biome,” although there is not yet data to support this theory.
The microbiome theory is gaining so much steam in academia that a coalition of four U.S. research centers called the MS Microbiome Consortium recently formed to investigate the role of gut microorganisms in the disease. The group presented data in Boston showing significantly different gastrointestinal bacterial populations in patients treated with the MS drug glatiramer acetate compared with untreated subjects. How exactly the drug suppresses MS activity is unknown but the findings suggest that perhaps it works in part by altering gut flora and, as a result, suppressing abnormal immune activity. “The gut is well-positioned for an important role in the development of autoimmune disease, including MS.,” says Ilana Katz Sand, an assistant professor of neurology at Mount Sinai Medical Center in New York City and member of the MS Microbiome Consortium. “But important questions remain, such as how MS medications affect the microbiome, how an individual’s microbiome may affect treatment responses, whether particular bacterial species are associated with more severe disease and ultimately whether we can manipulate the microbiome to benefit our patients.”
Katz Sand says that dietary and probiotic approaches to treating MS are worth pursuing, as is a less palatable approach: fecal transplantation. Yet answers in science and medicine are rarely simple, she added, pointing out that in all likelihood MS arises from a complicated confluence of genetic and environmental influences that might ultimately trigger autoimmune activity. Beyond just our gut flora well over 100 genetic variants—many related to immune function—are now known to contribute to the disease as are external factors including vitamin D deficiency (MS is more common at higher latitudes), smoking and increased salt intake.
Further confounding our ability to pinpoint root causes is that our genetic code influences how our bodies and brains respond to these external factors. It could be that both genes and environmental stimuli lead to pathologic microbiomes or that some unfortunate combination of these factors leads to a common autoimmunologic pathway that ravages myelin. “We know the microbiome shapes our immune system and that MS is an immune-mediated disease. We also know that genes influence our microbiomes and immune systems,” says David Hafler, professor of neurology and immunobiology at Yale University School of Medicine who was at the conference but not involved in the microbiome work presented. But there must be nongenetic factors contributing to the disease, too, given that the incidences of MS and other autoimmune disorders are increasing.
“Maybe it’s a lot of little factors like low vitamin D, increased body mass index and increased salt intake,” Hafler says, “but I wouldn’t be surprised if it was one big thing, much like how H. pylori was found to cause ulcers. No one’s identified a clear bug that’s driving MS but I think it’s important we keep looking.”
segunda-feira, 19 de maio de 2014
Mice with multiple sclerosis-like condition walk again after human stem cell treatment
May 15, 2014
University of Utah Health Sciences
Mice severely disabled by a condition similar to multiple sclerosis (MS) were able to walk less than two weeks following treatment with human neural stem cells. The finding uncovers potential new avenues for treating MS. When scientists transplanted human stem cells into MS mice, they predicted the cells would be rejected, much like rejection of an organ transplant. Expecting no benefit to the mice, they were surprised when the experiment yielded spectacular results.
1) Multiple sclerosis (MS) impairs nerve function by damaging myelin, an insulating layer that surrounds nerves. MS mice can't move well. 2) Human neural stem cells injected into MS mice stimulate the mouse's own cells to repair the damage. 3) Nerve cell function is restored. MS mice can walk and run.
Mice severely disabled by a multiple sclerosis (MS) -- like condition could walk less than two weeks following treatment with human stem cells. The finding, which uncovers new avenues for treating MS, will be published online on May 15, 2014, in the journal Stem Cell Reports.
When scientists transplanted human stem cells into MS mice, they predicted the cells would be rejected, much like rejection of an organ transplant.
Expecting no benefit to the mice, they were surprised when the experiment yielded spectacular results.
"My postdoctoral fellow Dr. Lu Chen came to me and said, 'The mice are walking.' I didn't believe her," said co-senior author, Tom Lane, Ph.D., a professor of pathology at the University of Utah, who began the work at University of California, Irvine.
Within just 10 to 14 days, the mice regained motor skills. Six months later, they still showed no signs of slowing down.
"This result opens up a whole new area of research for us," said co-senior author Jeanne Loring, Ph.D., co-senior author and professor at The Scripps Research Institute in La Jolla, Calif.
More than 2.3 million people worldwide have MS, a disease where the immune system attacks myelin, an insulation layer surrounding nerve fibers. The resulting damage inhibits nerve impulses, producing symptoms that include difficulty walking, impaired vision, fatigue and pain.
The MS mice treated with human stem cells experience a reversal of symptoms. Immune attacks are blunted, and damaged myelin is repaired, explaining their dramatic recovery. The discovery could help patients with latter, or progressive, stages of the disease, for whom there are no treatments.
Counterintuitively, the researchers' original prediction that the mice would reject the stem cells, came true. There are no signs of the cells after one week. In that short window, they send chemical signals that instruct the mouse's own cells to repair the damage caused by MS. This realization could be important for therapy development.
"Rather than having to engraft stem cells into a patient, which can be challenging, we might be able to put those chemical signals into a drug that can be used to deliver the therapy much more easily," said Lane.
With clinical trials as the long-term goal, the next steps are to assess durability and safety of the stem cell therapy in mice.
"I would love to see something that could promote repair and ease the burden that patients with MS have," said Lane.
"This result opens up a whole new area of research for us," said co-senior author Jeanne Loring, Ph.D., co-senior author and professor at The Scripps Research Institute in La Jolla, Calif.
More than 2.3 million people worldwide have MS, a disease where the immune system attacks myelin, an insulation layer surrounding nerve fibers. The resulting damage inhibits nerve impulses, producing symptoms that include difficulty walking, impaired vision, fatigue and pain.
Story Source:
The above story is based on materials provided by University of Utah Health Sciences. Note: Materials may be edited for content and length.
Journal Reference:
- Lu Chen, Ronald Coleman, Ronika Leang, Ha Tran, Alexandra Kopf, Craig M. Walsh, Ilse Sears-Kraxberger, Oswald Steward, Wendy B. Macklin, Jeanne F. Loring, Thomas E. Lane. Human Neural Precursor Cells Promote Neurologic Recovery in a Viral Model of Multiple Sclerosis. Stem Cell Reports, 2014; DOI: 10.1016/j.stemcr.2014.04.005