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Archive - Feb 18, 2015

Duke Results Suggest CRISPR/Cas9-Enabled Gene Editing Might Be Used to Effectively Treat Over Half of Patients with Duchenne Muscular Dystrophy (DMD)

Duke researchers have demonstrated a genetic therapeutic technique that has the potential to treat more than half of the patients suffering from Duchenne muscular dystrophy (DMD). One of the challenges of treating DMD is that the disease can be caused by mutations in a number of different DNA sequences, and few of these mutations occur with any substantial frequency. The new technique, however, gets around this sticking point by targeting a large region of the (DMD) gene that contains many different mutations. The new study was published online on February 18, 2015 in Nature Communications. The article was entitled, “"Multiplex CRISPR/Cas9-Based Genome Editing for Correction of Dystrophin Mutations That Cause Duchenne Muscular Dystrophy." "There are no effective therapies currently available for people with DMD," said Dr. Charles Gersbach, Assistant Professor of Biomedical Engineering at Duke University. "DMD patients are in a wheelchair by age 10 and typically die in their 20s. They have nothing to stop this right now, and we're trying to work on that." DMD is caused by problems with the body's ability to produce dystrophin, a long-chain protein that binds the interior of a muscle fiber to its surrounding support structure. Dystrophin is coded by a gene with 79 genetic "chunks" called exons. If any one exon incurs a debilitating mutation, the dystrophin chain does not get built. Without dystrophin providing support, muscle tends to shred and slowly deteriorate. The disease affects one in 3,500 newborn males. The mutation is on the X chromosome so female children with two copies of X should have at least one functioning copy of the gene.

Doncaster Ichthyosaur Fossil Identified As New Species; Swam the Seas for Millions of Years During the Triassic, Jurassic, and Cretaceous Periods

The fossil had been in the collections of Doncaster Museum and Art Gallery for more than 30 years until Dr. Dean Lomax, a yong paleontologist and Honorary Scientist at The University of Manchester, UK, uncovered its hidden secrets. Dr. Dean first examined the fossil in 2008 when he noticed several abnormalities in the bone structure which made him think he had something previously unidentified. Working with Professor Judy Massare of Brockport College, New York, he spent over five years travelling the world to check his findings and a paper explaining the discovery was published online recently in the Journal of Vertebrate Paleontology. Dr. Dean said: "After examining the specimen extensively, both Professor Massare and I identified several unusual features of the limb bones (humerus and femur) that were completely different [from] any other ichthyosaur known. That became very exciting. After examining perhaps over a thousand specimens, we found four others with the same features as the Doncaster fossil." Similarly shaped to dolphins and sharks, ichthyosaurs, which are often misidentified as “swimming dinosaurs,” swam the seas of the earth for millions of years during the Triassic, Jurassic, and Cretaceous periods, before being wiped out. The Doncaster fossil is between 189 million and 182 million years old, from a time in the early Jurassic period called the Pliensbachian. It is the world's most complete ichthyosaur of this age. "The recognition of this new species is very important for our understanding of ichthyosaur species diversity during the early Jurassic, especially from this time interval,” Dr. Dean added.

Mucus Retained in Goblet Cells of Cystic Fibrosis Patients Leads to Potentially Deadly Infections; New Finding Could Lead to Improved Treatments

Cystic fibrosis (CF) is a genetic disorder that affects one out of every 3,000 children in populations of Northern European descent. One of the key signs of CF is that mucus lining the lungs, pancreas, and other organs is too sticky, which makes it difficult for the organs to work properly, and the CF mucus in the lungs attracts bacteria and viruses resulting in chronic infections. Researchers at the University of Missouri-Columbia (MU-Columbia) recently found that CF mucus actually gets stuck inside some of the cells (goblet cells) that create it, rather than simply becoming stuck on the outside linings of organs. Dr. Lane Clarke, a Professor of Biomedical Sciences in the MU College of Veterinary Medicine, says that now that it is better understood how mucus becomes trapped in the body, scientists can begin working on potential treatments for patients with CF that help cells remove the sticky mucus more quickly. "Normally, special cells (goblet cells) create mucus and easily push it out to the linings of the organs where it belongs," said Dr. Clarke, who also is a Dalton Investigator in the MU Dalton Cardiovascular Research Center. "However, in CF patients, some cells that create the mucus fail to completely release the mucus, so the mucus becomes stuck halfway in and halfway out. This makes mucus clearance more difficult and potentially would allow bacteria to have an easy pathway to infecting cells to cause diseases like pneumonia." Dr. Clarke also examined the characteristics of mucus stored within the cells and found that it is not as acidic as in normal cells. "Previously, CF researchers disagreed as to whether CF cells also have a defect in properly acidifying areas inside cells," Dr. Clarke said.

DNA Damage Causes Immune Reaction and Inflammation, and Is Linked to Cancer Development; Crucial Clues to New Understanding Come from Rare Genetic Disease Ataxia Telangiectasia (AT)

For the first time, scientists from Umeå University have shown the importance of DNA damage in fine-tuning our innate immune system and hence the ability to mount the optimal inflammatory response to infections and other biological dangers. The study was published in the February 17, 2015 issue of Immunity. The title of the article is “DNA Damage Primes the Type I Interferon System via the Cytosolic DNA Sensor STING to Promote Anti-Microbial Innate Immunity.” The research group of Dr. Nelson Gekara, within the Laboratory for Molecular Infection Medicine Sweden (MIMS) at Umeå University, is interested in understanding how the innate immune system, our first line of defense, is regulated and how defects in the innate immune system contribute to infectious and inflammatory diseases. Our immune system does not lie idle waiting to be attacked before it responds. Even in the absence of infections, our immune system is in a constant state of alert. Among the immune mediators that are constantly produced at low levels, and that keep our immune system awake, are a group of factors called type I interferons. A very delicate balance in the production of type I interferons is essential for health: insufficient production results in susceptibility to viral infections, while excessive production normally leads to autoimmune/inflammatory diseases. One of the questions Dr. Gekara´s lab has been investigating is aimed at understanding the signaling processes that control type I interferon production and, in particular, to identify the endogenous "danger signals" that constantly trigger basal production of interferons and therefore keep our immune system in a "ready-to-attack" state. The clue to answering this question came from a rare, but complex disease called ataxia telangiectasia (AT).

Mutated Genes Causing Autism in Children Are Linked to RhoA Biochemical Pathway That Regulates Neuronal Migration and Brain Morphogenesis during Early Stages of Brain Development; Plans to Test RhoA Pathway Inhibitors Using a Stem Cell Model of Autism

Scientists at the University of California, San Diego (UCSD) School of Medicine have found that mutations that cause autism in children are connected to a pathway that regulates brain development. The research, led by Lilia Iakoucheva, Ph.D, Assistant Professor in the Department of Psychiatry, was published in the February 18, 2015 issue of Neuron. The article was entitled “Spatiotemporal 16p11.2 Protein Network Implicates Cortical Late Mid-Fetal Brain Development and KCTD13-Cul3-RhoA Pathway in Psychiatric Diseases.” The researchers studied a set of well-known autism mutations called copy number variants or CNVs. They investigated when and where these mutated genes were expressed during brain development. “One surprising thing that we immediately observed was that different CNVs seemed to be turned on in different developmental periods,” said Dr. Iakoucheva. Specifically, the scientists noted that one CNV located in a region of the genome known as 16p11.2 (on chromosome 16), contained genes active during the late mid-fetal period. Ultimately, the researchers identified a network of genes that showed a similar pattern of activation including KCTD13 within 16p11.2 and CUL3, a gene from a different chromosome that is also mutated in children with autism. “The most exciting moment for us was when we realized that the proteins encoded by these genes form a complex that regulates the levels of a third protein, RhoA,” said Dr. Iakoucheva. Rho proteins play critical roles in neuronal migration and brain morphogenesis at early stages of brain development. “Suddenly, everything came together and made sense.”

World’s Most Comprehensive Map of Human Genomics Unveiled Simultaneously in 24 Journals

Two dozen scientific papers published online simultaneously on Feb. 18, 2015 present the first comprehensive maps and analyses of the epigenomes of a wide array of human cell and tissue types. Epigenomes are patterns of chemical annotations to the genome that determine whether, how, and when genes are activated. Because epigenomes orchestrate normal development of the body, and disruptions in epigenetic control are known to be involved in a wide range of disorders, from cancer to autism to heart disease, the massive trove of data is expected to yield many new insights into human biology in both health and disease. The 24 papers describing human epigenomes will appear in print on Feb. 19, 2015 in the journal Nature and in six other journals under the aegis of Nature Publishing Group. Collectively, the papers are a culmination of years of research by hundreds of participants in the Roadmap Epigenomics Program (REP), first proposed in 2006 by academic scientists and key members of the National Institutes of Health. All will be freely available at Nature's Epigenome Roadmap website. "The DNA sequence of the human genome is identical in all cells of the body, but cell types--such as heart, brain, or skin cells--have unique characteristics and are uniquely susceptible to various diseases," said University of California, San Francisco's (UCSF’s) Joseph F. Costello, Ph.D., director of one of the four NIH Roadmap Epigenome Mapping Centers (REMC) that contributed data to the REP. "By guiding how genes are expressed, epigenomes allow cells carrying the same DNA to differentiate into the more than 200 types found in the human body." In cancer research, said Dr. Costello, the new data will hasten a merging of genomic and epigenomic perspectives that was already underway.

Microbial Metabolite of Linoleic Acid Meliorates Intestinal Inflammation; Potentially Helpful in Crohn Disease & Ulcerative Colitis

A Japanese research group has demonstrated that 10-hydroxy-cis-12-octadecenoic acid (HYA), a gut microbial metabolite of linoleic acid, has a suppressive effect on intestinal inflammation. HYA is expected to be practically applied as a functional food. Inflammatory bowel diseases (IBDs), including Crohn disease and ulcerative colitis, are hard to completely cure. Globally, IBDs affect more than 4 million people, today. However, Professor Soichi Tanabe (Graduate School of Biosphere Science, Hiroshima University) and his collaborators have demonstrated that 10-hydroxy-cis-12-octadecenoic acid (HYA), a gut microbial metabolite of linoleic acid, has a suppressive effect on intestinal inflammation. HYA is expected to be practically applied as a functional food. The results of this group’s research were published in the January 30, 2015 issue of The Journal of Biological Chemistry in an article entitled "A Gut Microbial Metabolite of Linoleic Acid, 10-Hydroxy-Cis-12-Octadecenoic Acid, Ameliorates Intestinal Epithelial Barrier Impairment Partially via GPR40–MEK–ERK Pathway." IBD patients characteristically demonstrate increased expression of tumor necrosis factor receptor-2 (TNFR-2) and an upregulated inflammatory NF-κB pathway. Professor Tanabe and his colleagues have demonstrated that HYA binds to a G protein-coupled receptor (GPR40) and meliorates intestinal epithelial barrier impairment in an intestinal epithelial cell line, Caco-2 cells; oral administration of HYA also alleviates colitis in mice. The physiological activity of gut microbial metabolites has recently attracted considerable attention. HYA may be useful in the treatment of tight junction-related disorders, such as IBD.