Gene linked to interferon-beta treatment(18/05/15)
A new study led by investigators at Brigham and Womens Hospital (BWH) reports the discovery of a genetic variant associated with a patients likelihood of responding to interferon-beta, one of the medications used in treating multiple sclerosis.
Published in the Annals of Neurology, the study also presents evidence that the affected gene, SLC9A9, may have a broader role in regulating the development and activity of certain immune cells that play important roles in inflammatory diseases like MS.
The variant most predictive of whether or not a patient would respond to the drug was found in the gene SLC9A9.
"This study highlights the fact that genetic variation has a role in the course of a patient's MS, but that this role is modest and will require much larger studies to be understood in detail," said Philip De Jager, MD, PhD, who directs the Program in Translational NeuroPsychiatric Genomics at the Ann Romney Center for Neurologic Diseases at BWH.
A large, ongoing study of MS patients called CLIMB, based out of the Partners Multiple Sclerosis Center, was integral to the current work and will continue to follow patients over the course of treatment to identify predictors of future disease course and the effectiveness of treatments.
Additional support was provided by the National MS Society, Fondazione Italiana Sclerosi, the French MS society Association pour la recherche sur la sclerose en plaques, the Club francophone de la SEP, and the Reseau francais pour la genetique de la SEP.
De Jager is a recipient of the prestigious Harry Weaver Neuroscience Scholar of the National MS Society.
Source: Demanjo Copyright © Demanjo 2015 (18/05/15)
Genetic risk factor uncovered(05/03/15)
Researchers at the University of Illinois at Chicago have identified a genetic variation that in women significantly increases their risk of developing multiple sclerosis. The report is published in the journal ASN Neuro.
The variant occurs almost twice as often among women with MS as in women without the disease, making it "one of the strongest genetic risk factors for MS discovered to date," said senior author Doug Feinstein, professor of anesthesiology at UIC and research biologist at the Jesse Brown VA Medical Center.
Feinstein and his colleagues were able to test three sisters among a group of five siblings between the ages of 23 and 26, all diagnosed with MS. They found the variant in all three they tested.
What they found was a genetic change known as a single nucleotide polymorphism, or SNP - a change in a single base-pair of the DNA - in a gene called STK11, which plays a role in tumor suppression and is believed to have several roles in brain function.
Genetic factors are known to influence the risk of developing MS. The UIC researchers were led to this variant thanks to a woman participating in another study at UIC. In a casual conversation, the woman told study coordinator Anne Boullerne that she and her four siblings - three sisters, including twins, and a brother - all had multiple sclerosis.
"This is an extremely rare occurrence," said Boullerne, who is research assistant professor of anesthesiology and lead author on the paper. She said she could find no published studies with five siblings with multiple sclerosis.
"I was immediately interested in the possibility of a genetic study of the family because all five siblings - an entire generation - are affected by MS, and so we could have a very good chance of discovering key genes related to inheritance of the disease."
The woman also described among her sisters and the women on her mother's side of the family a prevalence of diseases associated with Peutz-Jeghers syndrome, a rare genetic disorder caused by mutations in the STK11 gene and characterized by an increased risk for certain cancers, including breast, ovary and colon cancers.
A literature search by Feinstein uncovered an article that described how mice with a disabled STK11 gene had a higher incidence of loss of myelin from the nerves of the central nervous system - a defining characteristic of MS.
The woman consented to a complete DNA-sequencing of her genome. Boullerne took a close look at the STK11 gene, where she discovered the SNP. She next obtained consent to sequence the genomes of two of the woman's sisters and found they also carried the same SNP.
To determine if the SNP could be a contributing factor to the siblings' multiple sclerosis, the researchers screened DNA samples from 1,400 people - 750 with MS and 650 without - provided by Jorge Oksenberg at the University of California, San Francisco, who is a leading expert on the genetics of MS. They found that the SNP was 1.7 times as prevalent in women with MS as in women without the disease, making it one of the highest known genetic risk factors for MS.
Based on their analysis, the researchers estimate that the STK11 SNP is present in about 7 percent of the general population. But because far fewer people develop MS, other genetic or non-genetic factors must play a role in the development of the disease, Feinstein said.
Feinstein and Boullerne plan to continue their hunt for other genetic factors that may contribute to MS among the five siblings and possibly their parents. They will also investigate the function of the STK11 gene in the lab, which could reveal molecular pathways involved in multiple sclerosis.
Source: Medical Xpress © Medical Xpress 2011-2015, Science X network (05/03/15)
What role does our genetic makeup play in autoimmune diseases – diseases like lupus and multiple sclerosis wherein the body’s own immune system turns on it? That question has plagued researchers for decades. However, a new gene mutation has been discovered that could help scientists map an autoimmune disease in the body and find out how the immune system is inappropriately triggered to attack itself.
Researchers in a new study at the University of Edinburgh have honed in on five of 89 independent variations in human genetics that are believed to be responsible for autoimmune conditions, from celiac disease and multiple sclerosis to rheumatoid arthritis and asthma. Understanding how these mechanisms work could help scientists to develop new treatments.
The team found that a mutation in the ADAR1 gene causes a defect in an “alarm system” in cells that normally protects the body from viruses and other infections by triggering the body’s immune system to fight. The mutation causes this alarm system to be tripped by the cell’s own molecules, causing the immune system to attack – the uniting trait of all autoimmune diseases.
The ADAR1 mutation and the others identified by the researchers together helped reveal the system that helps the body to differentiate between normal RNA and RNA from foreign organisms. The exact problem with this mechanism that characterizes autoimmune disorders differs for each, as the body’s way of attacking itself is unique and presents no two symptoms that are exactly alike, even within families.
There are more than 80 types of autoimmune diseases affecting 5-8 percent of the American population. There are no obvious patterns in autoimmune disease; individuals of any age and sex may be affected, making the process of pin-pointing important genes extremely difficult.
Though autoimmune diseases vary wildly in their specifics, a family history of autoimmune disorders can indicate a genetic predisposition that may increase the risk to develop an autoimmune disease. This risk persists even when dealing with different autoimmune diseases. In a predisposed family, a woman may have rheumatoid arthritis and one of her siblings may develop lupus. While diseases can be passed down from parent to child, it doesn’t automatically mean someone will get the same disorders their family members suffer from. The exact nature of the immune response and how the body deals with it varies from case to case.
Though identifying genetic common ground is essential to a better understanding and treatment of autoimmune diseases, environmental factors can also play an important role in triggering the onset of disease. A few such triggers have been identified, including several drugs that are associated with some forms of lupus, thrombocytopenia, and hemolytic anemia. Sometimes infections can trigger an autoimmune disease, such as rheumatic fever caused by a streptococcal infection and Guillain-Barre syndrome caused by chlamydia. In addition, a great deal of circumstantial evidence suggests that viruses may play a role in initiating some autoimmune diseases. Despite these known triggers, most cases of autoimmune disease cannot be linked to clear evidence of a particular environmental trigger.
The new ability the researchers found to associate specific genetic variants with autoimmune disease broadly and to probe will enable medical researchers to more precisely target therapeutic interventions in autoimmune diseases in order to dampen fired-up immune responses. Finding the ADAR1 mutation is a huge step toward learning more about autoimmune diseases and what exactly they do to the human body when active. Mapping the relevant mutations and their chemical signatures in the body helps reveal the exact mechanisms by which autoimmune diseases occur and cause harm – hopefully providing new targets for doctors trying to treat these stubborn and pernicious disease.
Source: The Genetic Literacy Project. © 2014 The Genetic Literacy Project (05/12/14)
A multifaceted team of researchers developed a new mathematical formula to scour existing DNA databases in order to determine why inherited DNA variations contribute to disease. The sequencing techniques they developed examined epigenetic characteristics of specialised immune cells.
Previously, the researchers had used a similar tool to study 21 different autoimmune diseases, and they were able to apply that method to the current project.
The researchers probed 39 genome-wide association studies (GWAS) – which each enlist thousands of participants – to identify DNA blocks implicated in genetic factors for diseases. GWAS rarely point to altered proteins, however. The researchers believe this is because only a few protein-encoding gene variants with these DNA codes have been investigated, let alone associated with autoimmune disease.
Investigators found the presence of specific gene variants differ among autoimmune diseases, which can further alter the functional ability of the immune system. This remained true even though the genetic variants are not within genes.
The majority of DNA changes related to autoimmune diseases occurred in the section of DNA known as “enhancers.” The enhancers of DNA – which is typically shaped in stringy molecules – allow DNA to fold so the various proteins can interact with each other. The enhancers also allow the bending of DNA to activate switches that can turn on specific genes. The enhancers the researchers identified as essential to DNA interaction had not been previously thought to have any functional role.
“Once again, research is revealing new meaning in the world of DNA once thought of as junk — short, seemingly random DNA sequences that in fact serve meaningful roles in human physiology,” Alex Marson, MD, PhD, the corresponding author for the study, said in a press release.
After combing through data collected about DNA patterns, the researchers determined T helpers, a type of immune cell, may be a response to stimuli that increase the risk of autoimmune diseases. The researchers believe MS therefore stems from the immune system, and not from genetic variants associated with the nervous system.
“This is highly consistent with the new multiple sclerosis treatments that work on the immune system, suggesting that we finally have a good handle as to the underlying causes of MS,” David A. Hafler, MD, co-first author of the study, continued in the press release. He went on to explain that the immune system plays a primary role in MS, and is almost certainly an autoimmune disease.
The researchers hope these findings can ultimately lead to better diagnosis and improved treatments.
Source: HCPLive © Health Care Professionals 2014 (14/11/14)
Researchers from UC San Francisco, the Broad Institute of MIT and Harvard, and Yale School of Medicine recently developed a software tool that helps researchers understand the complex genetic origins of many autoimmune diseases and, ultimately, to better diagnose and treat them. The study was published yesterday in Nature.
One in every twelve Americans are affected with autoimmune diseases such as multiple sclerosis (MS), type 1 diabetes, rheumatoid arthritis, and asthma. What happens in these kinds of diseases is that the immune system begins to attack the body’s own cells and tissues. This new study connects insights into genetics with the origins of these diseases — a connection that the tool’s creators believe will serve as a key asset for diagnosing and treating autoimmune diseases like MS.
The researchers developed a mathematical tool to more intensively probe existing DNA databases, which in turn has allowed them to discover that certain DNA variations contribute to the development of diseases and, if inherited, can signify a higher predisposition for becoming sick.
Through their method, the researchers analyzed data from previous studies regarding 21 autoimmune diseases, and thoroughly examined their scientific fundamentals. From this analysis, they found specific immune cells that are actually responsible for the diseases.
Data from 39 large-scale studies called GWAS, the genome-wide association studies, was analyzed. Many GWAS analyses have been conducted, and each one enlisted a large number of participants allowing researchers to identify large blocks of DNA within the human genome and within each genetic variant related to a disease that might represent risk factors. Until now, the GWAS examination has rarely pointed to altered proteins, and few protein-encoding gene variants in a large amount of DNA evidence like this one were associated with the diseases under investigation.
The genetic risks identified through GWAS studies suggest that the answer may reside in DNA variations that are not within genes. Therefore, medical benefits have emerged from large-scale studies of human genetic variations conducted in the wake of the Human Genome Project.
Researchers figured that specific genetic variants in several autoimmune diseases can change patterns of the genes’ activity in ways that affect immune system functions. This study focused on “epigenetic” characteristics in which genes’ activity is affected, but the DNA sequences of the affected genes remain untouched. As a result, these variations in DNA do not occur in genes’ zones; the majority occur in functional DNA fragments known as “enhancers.”
DNA can bend back by supporting itself in a chromosome’s structural proteins, and a piece of DNA, usually long and stringy, can interact with another strand. Enhancers fold in like this to bind to DNA switches and activate genes. The enhancers identified in this study and that play a role in the autoimmune diseases were DNA sequences different from DNA-sequence, which were previously thought to be crucial for enhancers to work and are a novelty, as they function as sequences that are actually functional.
Alex Marson, MD, PhD, UCSF Sandler Faculty Fellow and the author of the study, said in a press release: “Once again, research is revealing new meaning in the world of DNA once thought of as junk — short, seemingly random DNA sequences that in fact serve meaningful roles in human physiology.”
Mapping enhancers in specialized immune cells and tracking patterns of altered gene activation in GWAS studies allowed the researchers to associate this phenomena with the respective immune diseases. Many of them were found to be related to immune cells known as “T helpers.” The study suggests that genetic variation may be triggering a response from these immune cells to stimuli within their surroundings to increase the risk of autoimmunity.
Marson and his team link the cause of MS to the immune system and not to the genetic variations concerning the nervous system. Results show that MS is an autoimmune disease: “This is highly consistent with the new multiple sclerosis treatments that work on the immune system, suggesting that we finally have a good handle as to the underlying causes of MS,” said David A. Hafler, MD, professor of neurology and immunobiology, and chair of the Department of Neurology at Yale and Marson’s collaborator.
These new findings will ultimately “enable medical researchers to more precisely target therapeutic interventions in autoimmune diseases in order to dampen aberrantly fired-up immune responses,” cited from the UCSF press release.
The major funding for this study came from the National Institutes of Health and the National Multiple Sclerosis Society, and through it, Marson intends to understand how these newly identified DNA variants in enhancers affect cells and cause diseases, and how these consequences can be mitigated through DNA manipulation.
Source: Multiple Sclerosis News Today © Copyright 2014 BioNews Services, LLC (31/10/14)
Approximately 110 multiple genetic variations were previously identified by genome-wide association studies (GWAS) to be associated with Multiple Sclerosis (MS). Now, that number has increased, with more than 159 genetic variants identified, thanks to new research presented by Philip De Jager, M.D., of Brigham and Women’s Hospital, Harvard Medical School and the International MS Genetics Consortium at the ACTRIMS-ECTRIMS conference in Boston.
The team led by Dr. De Jager performed the first comprehensive meta-analysis of existing MS-GWAS, spanning approximately 14,000 individuals with the disease. The researchers identified unknown genetic variants, and further studies involving 2,000 individuals led to confirmation of 48 new variants — for now.
With the confirmed identification of these new genetic variants, the team proposed to understand how the variants relate to MS susceptibility. Dr. De Jager noted, “the majority of the MS genes seemed to be related to immune function and expressed on immune cells.” The authors hypothesized the new variants could be related with alterations to brain function. To test their hypothesis, they examined the newly genetic variants in older, MS-free postmortem frontal lobes’ tissues. “[This is] exciting because there are at least some disease effects that may be related to alteration of gene expression inside the brain,” commented the author. Since the analysis was performed with the whole tissue, at the moment the authors can’t confirm the source cell type for these genes, as Dr De Jager noted, “Some of these changes may be driven by changes in the brain’s immune cells like changes in the microglia.”
Notably, Dr. De Jager highlighted how certain genome regions harbor multiple different variants that impact the risk for MS. Hence, to develop reliable predictive tests for MS, it is crucial to study each of these variants and fully understand their functional impact on MS.
The current study explains less than half of the heritability of MS, so Dr. De Jagers’ team and the International MS Genetics Consortium are committed to identify more genetic variants for MS susceptibility and to study it thoroughly.
Source: Multiple Sclerosis News Today © Copyright 2014 BioNews Services, LLC (03/10/14)
Common mechanisms in neurodegeneration and neuroinflammation: a BrainNet Europe gene expression microarray study.
Durrenberger PF, Fernando FS, Kashefi SN, Bonnert TP, Seilhean D, Nait-Oumesmar B, Schmitt A, Gebicke-Haerter PJ, Falkai P, Grünblatt E, Palkovits M, Arzberger T, Kretzschmar H, Dexter DT, Reynolds R.
Neurodegenerative diseases of the central nervous system are characterised by pathogenetic cellular and molecular changes in specific areas of the brain that lead to the dysfunction and/or loss of explicit neuronal populations.
Despite exhibiting different clinical profiles and selective neuronal loss, common features such as abnormal protein deposition, dysfunctional cellular transport, mitochondrial deficits, glutamate excitotoxicity, iron accumulation and inflammation are observed in many neurodegenerative disorders, suggesting converging pathways of neurodegeneration.
We have generated comparative genome-wide gene expression data, using the Illumina HumanRef 8 Beadchip, for Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, Parkinson's disease, and schizophrenia using an extensive cohort (n = 113) of well-characterized post-mortem brain tissues.
The analysis of whole-genome expression patterns across these major disorders offers an outstanding opportunity not only to look into exclusive disease-specific changes, but more importantly to look for potential common molecular pathogenic mechanisms.
Surprisingly, no dysregulated gene that passed our selection criteria was found in common across all six diseases. However, 61 dysregulated genes were shared when comparing five and four diseases.
The few genes highlighted by our direct gene comparison analysis hint toward common neuronal homeostatic, survival and synaptic plasticity pathways. In addition, we report changes to several inflammation-related genes in all diseases.
This work is supportive of a general role of the innate immune system in the pathogenesis and/or response to neurodegeneration.
Source: J Neural Transm. 2014 Aug 13. [Epub ahead of print] & Pubmed PMID: 25119539 (21/08/14)
Evidence found in both human multiple sclerosis patients and experimental mouse models, according to research published in the American Journal of Pathology.
A new study published in The American Journal of Pathology identifies a novel gene that controls nerve conduction velocity. Investigators report that even minor reductions in conduction velocity may aggravate disease in multiple sclerosis (MS) patients and in mice bred for the MS-like condition experimental autoimmune encephalomyelitis (EAE).
A strong tool for investigating the pathophysiology of a complex disease is the identification of underlying genetic controls. Multiple genes have been implicated as contributing to the risk of developing MS. Unlike studies that have focused on genetic regulators of inflammation, autoimmunity, demyelination, and neurodegeneration in MS, this study focused on nerve conduction velocity. Investigators found that polymorphisms of the inositol polyphosphate-4-phosphatase, type II (Inpp4b) gene affect the speed of nerve conduction in both mice with EAE and humans with MS.
"Impairment of nerve conduction is a common feature in neurodegenerative and neuroinflammatory diseases such as MS. Measurement of evoked potentials (whether visual, motor, or sensory) is widely used for diagnosis and recently also as a prognostic marker for MS," says lead investigator Saleh M. Ibrahim, MD, PhD, of the Department of Dermatology, Venereology, and Allergology of the University of Lubeck (Germany).
Using several genomic approaches, the investigators narrowed their search to the genetic region controlling the enzyme inositol-polyphosphate-4-phosphatase II (INPP4B), the product of which helps to regulate the phosphatidyl inositol signaling pathway. Enzymes in this family are involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival, and intracellular communication.
In one series of experiments, the researchers analyzed the genetic locus EAE31, which previously had been shown to control the latency of motor evoked potentials and clinical onset of EAE in mice. Using advanced techniques including congenic mapping, in silico haplotype analyses (computer simulations), and comparative genomics (from rats, mice and humans), they were able to "finemap" the focus to Inpp4b as the quantitative trait gene for EAE31.
When the investigators analyzed this region in eight different strains of mice, they found they could divide the strains into two groups based on differences in amino acid sequences. The strains with the longer-latency SJL/J allele had the two amino acids (arginine and proline), whereas those with the shorter-latency C57BL/10S allele had others (serine and histidine). "These data suggest that Inpp4b structural polymorphism is associated with the speed of neuronal conduction," comments Dr. Ibrahim.
In another experiment, the scientists compared motor conduction velocity in genetically modified mice with a mutant Inpp4b gene to that of control mice. The nerve conduction in this group was slower than in the control group.
Finally, the investigators studied INPP4B polymorphisms in MS patients. They looked at two cohorts: one from Spain (349 cases and 362 controls) and a second from Germany (562 cases and 3,314 controls). The association between the INPP4B polymorphisms and susceptibility to MS was statistically significant when the cohorts were pooled. However, although the Spanish cohort showed a strong association between INPP4B and MS, the association was weaker in the German cohort. "The exact reason for the diverging effect across these populations remains unresolved," states Dr. Ibrahim.
In an accompanying commentary, Hans Lassmann, MD, of the Center for Brain Research of the Medical University of Vienna (Austria) notes, "This study represents an interesting example of how minor changes in conduction velocity, which do not result in a clinical phenotype in control populations, may aggravate disease in conditions such as EAE or MS." In other words, impaired nerve conduction may have a greater impact on those with MS compared to healthy individuals. Noting that the study reported no major loss of myelin in animals carrying the mutant allele, Dr. Lassmann comments that it is still unclear which neurobiological mechanisms underlie the INPP4B-associated impaired conduction. One suggestion is that INPP4B may be involved in calcium ion signaling within synapses, affecting neurotransmitter release.
Source: EurekaAlert! Copyright ©2014 by AAAS (13/08/14)
A key difference in the brains of male and female MS patients may explain why more women than men get the disease, a study suggests.
Scientists at Washington University School of Medicine in the US found higher levels of protein S1PR2 in tests on the brains of female mice and dead women with MS than in male equivalents.
Four times more women than men are currently diagnosed with MS.
Experts said the finding was "really interesting".
MS affects the nerves in the brain and spinal cord, which causes problems with muscle movement, balance and vision. It is a major cause of disability, and affects about 100,000 people in the UK.
Abnormal immune cells attack nerve cells in the central nervous system in MS patients.
There is currently no cure, although there are treatments that can help in the early stages of the disease.
Researchers in Missouri looked at relapsing remitting MS, where people have distinct attacks of symptoms that then fade away either partially or completely. About 85% of people with MS are diagnosed with this type.
Scientists studied the blood vessels and brains of healthy mice, mice with MS, and mice without the gene for S1PR2, a blood vessel receptor protein, to see how it affected MS severity.
They also looked at the brain tissue samples of 20 people after they had died.
They found high levels of S1PR2 in the areas of the brain typically damaged by MS in both mice and people.
The activity of the gene coding for S1PR2 was positively correlated with the severity of the disease in mice, the study said.
Scientists said S1PR2 could work by helping to make the blood-brain barrier, in charge of stopping potentially harmful substances from entering the brain and spinal fluid, more permeable.
A more permeable barrier could let attacking cells, which cause MS, into the central nervous system, the study said.
Prof Robyn Klein, of the Washington University School of Medicine, said: "We were very excited to find the molecule, as we wanted to find a target for treatment that didn't involve targeting the immune cells.
"This link [between MS and S1PR2] is completely new - it has never been found before."
Prof Klein said she did not know why the levels of S1PR2 were higher in women with MS, adding she had found oestrogen had "no acute role".
She would be looking at taking her findings to clinical trials in the "next few years", she added.
Dr Emma Gray, of the MS Society, said: "We don't yet fully understand why MS affects more women than men, and it's an area that's intrigued scientists, and people with MS, for many years.
"A number of theories have been suggested in the past, including the influence of hormones or possible genetic factors - and this study explores one such genetic factor in further detail, which is really interesting."
She said understanding the causes of MS was a "priority" for the MS Society in the UK, and could be "crucial" in finding new treatments.
The research was published in the Journal of Clinical Investigation.
Source: BBC News © British Broadcasting Corporation 2014 (09/05/14)
The diagnosis and treatment of Multiple Sclerosis (MS) have dramatically improved over recent decades due to scientific advancements, yet MS persists as one of the most disabling neurological disorders, having a significant impact on young adults - the age group most affected by the disease.
Continuing medical education provider, EXCEMED - Excellence in Medical Education, will draw leading international experts in MS to explore the roles of genetics and environment in MS pathology. The conference, "Multiple sclerosis: Improving patient outcomes through scientific and clinical advances" takes place in Dubai, United Arab Emirates, from 9 to 10 May 2014.
"This meeting will present the latest epidemiological and genetic knowledge about MS and link it to pathology and the practical management of therapy for people with MS" says Professor David Bates, Department of Neurology, Royal Victoria Infirmary, Newcastle upon Tyne, UK, and - scientific organizer of the event.
"We are proud to gather, year after year, an outstanding international panel of experts in neurology and MS research in order to contribute to the debate from the perspective of clinical practices. The goal is to identify the most appropriate treatments for this disease," says Professor Giancarlo Comi, President of the EXCEMED Scientific Committee and Professor in Neurology at University Vita-Salute San Raffaele, Milan, Italy.
The scientific programme of the event offers three sessions and six workshops: Session one will address basic research in MS pathogenesis including epidemiology, risk factors, genetics of MS and mechanism and prevention of neurodegeneration. Session two will address clinical approaches to MS and session three will deal with therapeutic management. The six workshops will be attended in rotation by each participant to allow for optimal exchange of opinions and a deeper understanding of the different MS related topics.
Source: Digital Journal copyright © 2014 digitaljournal.com (09/05/14)
New pharmaceuticals to fight autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis and psoriasis, may be identified more effectively by adding genome analysis to standard drug screening, according to a new study by a research team led by UC San Francisco and Harvard researchers, in collaboration with Tempero and GlaxoSmithKlein.
In a study reported online April 17, 2014 in the journal Immunity, the scientists combined drug screening with state-of-the-art techniques for analyzing the genome, leading to three small molecules that improved symptoms in a mouse form of multiple sclerosis.
The three potential drug candidates, selected from a large library of screened chemicals, each knocked down the response of Th17 cells, a type of immune cell that drives many autoimmune diseases by attacking normal cells in the body. More specifically, the drugs homed in on an essential molecule within the Th17 cells.
"We examined what makes Th17 cells – which play a crucial role in multiple autoimmune diseases – distinct from other closely related T cells within the immune system," said Alexander Marson, MD, PhD, a leading T cell expert and member of the UCSF Diabetes Center. "Then we investigated several small molecules that inhibit the development and function of these cells. When the Th17 cells were hit by these molecules we saw less severe multiple-sclerosis-like symptoms in the mice."
The research team, led by Marson and Vijay K. Kuchroo, PhD, an immunologist at Brigham and Women's Hospital in Boston and Harvard Medical School, combined powerful techniques to shed light on a class of protein molecules within cells known as transcription factors.
Drug designers have rarely targeted transcription factors. Each transcription factor binds to DNA at a unique set of locations along the 23 pairs of chromosomes, and thereby influences which genes are turned on and off to trigger the protein production that drives cell development and function.
Different transcription factors shape the development of different types of T cells within the immune system, Marson and others are discovering. In their new study, Marson found that the transcription factor called ROR gamma t has a unique role in guiding development of Th17 cells, while inhibiting the development of other immune cells.
Preventing Th17 cells from developing by inhibiting the function of ROR gamma t appears to be an effective strategy for fighting autoimmune diseases, Marson said. "There already are drugs in clinical trials for autoimmune diseases – including psoriasis and rheumatoid arthritis – that are antibodies for IL-17 or IL-17 receptors," Marson said, referring to signaling molecules secreted by Th17 cells that can help trigger an attack our own healthy tissue, and the receptors that receive those signals. "This is an entirely different and promising approach to fight autoimmune disease," he said.
"Our studies map a path to targeting transcription factors and provide both insight into how transcriptional regulators shape the identity and affect the development of Th17 cells, and also into how different drug molecules might affect these regulatory circuits in the cells," he said.
To reveal the distinct and sometimes subtle effects of the drug candidates, the researchers studied the entire genome to see where ROR gamma t attached to DNA, which genes were activated or turned off as a result, and how these effects were altered by the drug candidates.
"Not only did we look at which genes are turned on and off, but we also systematically looked at DNA-binding sites across this genome," Marson said. "This pushes the boundary of what's typically done."
In addition to attaching to DNA, ROR gamma t has a pocket that looks like it should bind a hormone, Marson said. But what this hormone might be, and its effects, are unknown. The different drug candidates that inhibited Th17 development had different effects on ROR gamma t and resultant DNA binding and gene activation, possibly because of distinct interactions with the hormone-binding pocket, Marson said.
Analyzing the large data sets generated through such experiments could help pharmaceutical companies wading into development of drugs that target transcription factors to test the waters, Marson said, enabling drug developers to better understand mechanisms of drug action and to more easily see gene activity that could trigger side effects. According to Marson, "This is a new, broadly applicable approach for systematically evaluating leading drug candidates for autoimmune diseases."
Source: MedicalXpress © Medical Xpress 2011-2014 (02/05/14)
In patients with multiple sclerosis, the body turns on itself, launching an immune system attack that destroys the coating around nerve fibers in the central nervous system, leaving them exposed like bare wires. Similar to exposed electrical lines, the unprotected fibers touch and short out, leading to the neurodegenerative effects that are a hallmark of multiple sclerosis.
But what if doctors could stop the immune response that destroys the protective coating before the disease becomes debilitating? University of Florida researchers have received a $40,000 grant from the National Multiple Sclerosis Society to test a gene therapy technique in mice that aims to help the body not treat itself like a foreign invader — a process referred to as immune tolerance — in the earliest stages of multiple sclerosis. If the researchers can re-establish this tolerance, they could thwart the immune system attack, all with a technique that could be used on a wide number of patients.
"In previous years, we have learned a lot about how to manipulate tolerance using gene therapy," said Brad E. Hoffman, Ph.D., an assistant professor of pediatrics in the UF College of Medicine. "Tolerance is your body's way of not responding to substances that would otherwise induce an immune response so you don't have an immune response to everything. In multiple sclerosis, the body loses that ability to distinguish between self and not-self so it starts to attack its own nervous system cells."
About 2.5 million people worldwide suffer from multiple sclerosis, according to the National Multiple Sclerosis Society. The disease typically causes problems with vision, fatigue, speech, sensation and mobility. In advanced cases, multiple sclerosis can lead to blindness and paralysis.
Typically, gene therapy is used to correct a faulty gene in the body. In this case, researchers will deliver a gene responsible for a brain protein into the liver, via the harmless virus AAV, in hopes that it will spark production of regulatory T cells. These T cells, which suppress the immune system, are crucial because they could effectively shut down the immune attack in the brain, Hoffman said. The researchers are injecting the gene specifically into the liver because the organ filters out unwanted immune responses.
"Everything filters through the liver for detoxification," Hoffman said. "Because of this, the liver has an innate capacity to induce immune tolerance. We have learned in other gene therapy studies that it is possible for the liver to make cells tolerant to the gene you are putting in."
Other research teams across the country are trying to spark immune tolerance to combat multiple sclerosis, too. However those studies involve developing treatments personalized for specific patients. The UF researchers' work is novel because they hope to develop a technique that could be used on a wide number of patients.
"Everyone has different types of T regulatory cells and receptors," Hoffman said. "By injecting a gene responsible for a brain protein, we are allowing an individual's body to make the specific T regulatory cells it needs.
"If it works, this is potentially more clinically feasible, cost-effective and translatable for a large scale."
Although gene therapy has yet to be used to correct autoimmune disorders such as multiple sclerosis, the foundations for the study are rooted in research Hoffman's team has performed while studying gene therapy for hemophilia. During these studies, the team was able to induce immune tolerance in mice, and Hoffman hopes the techniques will one day be able to help people with multiple sclerosis, too.
"Will we be able to cure MS? That would be ideal, but our strategy is more likely to result in suppressing the immune response to the nervous system," he said. "If you suppress the immune response, you will suppress the neurodegenerative effects and hopefully maintain a higher quality of life."
Source: South Florida Sun-Sentinel Copyright © 2014, South Florida Sun-Sentinel (09/04/14)