BreakThrough Digest Medical News |
- Turning skin cells into brain cells
- New compound holds promise for treating Duchenne MD, other inherited diseases
- Dietary fiber alters gut bacteria, supports gastrointestinal health
- Mayo Clinic uses new approach to reverse multiple sclerosis in mice models
- New animal model for rheumatoid arthritis
| Turning skin cells into brain cells Posted: 27 Jun 2012 09:00 PM PDT
Johns Hopkins researchers, working with an international consortium, say they have generated stem cells from skin cells from a person with a severe, early-onset form of Huntington’s disease (HD), and turned them into neurons that degenerate just like those affected by the fatal inherited disorder.
By creating “HD in a dish,” the researchers say they have taken a major step forward in efforts to better understand what disables and kills the cells in people with HD, and to test the effects of potential drug therapies on cells that are otherwise locked deep in the brain. Although the autosomal dominant gene mutation responsible for HD was identified in 1993, there is no cure. No treatments are available even to slow its progression. The research, published in the journal Cell Stem Cell, is the work of a Huntington’s Disease iPSC Consortium, including scientists from the Johns Hopkins University School of Medicine in Baltimore, Cedars-Sinai Medical Center in Los Angeles and the University of California, Irvine, as well as six other groups. The consortium studied several other HD cell lines and control cell lines in order to make sure results were consistent and reproducible in different labs. The general midlife onset and progressive brain damage of HD are especially cruel, slowly causing jerky, twitch-like movements, lack of muscle control, psychiatric disorders and dementia, and ? eventually ? death. In some cases (as in the patient who donated the material for the cells made at Johns Hopkins), the disease can strike earlier, even in childhood. “Having these cells will allow us to screen for therapeutics in a way we haven’t been able to before in Huntington’s disease,” says Christopher A. Ross, M.D., Ph.D., a professor of psychiatry and behavioral sciences, neurology, pharmacology and neuroscience at the Johns Hopkins University School of Medicine and one of the study’s lead researchers. “For the first time, we will be able to study how drugs work on human HD neurons and hopefully take those findings directly to the clinic.” Ross and his team, as well as other collaborators at Johns Hopkins and Emory University, are already testing small molecules for the ability to block HD iPSC degeneration. These small molecules have the potential to be developed into novel drugs for HD. The ability to generate from stem cells the same neurons found in Huntington’s disease may also have implications for similar research in other neurodegenerative diseases such as Alzheimer’s and Parkinson’s. To conduct their experiment, Ross took a skin biopsy from a patient with very early onset HD. When seen by Ross at the HD Center at Hopkins, the patient was just seven years old. She had a very severe form of the disease, which rarely appears in childhood, and of the mutation that causes it. Using cells from a patient with a more rapidly progressing form of the disease gave Ross’ team the best tools with which to replicate HD in a way that is applicable to patients with all forms of HD. Her skin cells were grown in culture and then reprogrammed by the lab of Hongjun Song, Ph.D., a professor at Johns Hopkins’ Institute for Cell Engineering, into induced pluripotent stem cells. A second cell line was generated in an identical fashion in Dr. Ross’s lab from someone without HD. Simultaneously, other HD and control iPS cell lines were generated as part of the NINDS funded HD iPS cell consortium. Scientists at Johns Hopkins and other consortium labs converted those cells into generic neurons and then into medium spiny neurons, a process that took three months. What they found was that the medium spiny neurons deriving from HD cells behaved just as they expected medium spiny neurons from an HD patient would. They showed rapid degeneration when cultured in the lab using basic culture medium without extensive supporting nutrients. By contrast, control cell lines did not show neuronal degeneration. “These HD cells acted just as we were hoping,” says Ross, director of the Baltimore Huntington’s Disease Center. “A lot of people said, ‘You’ll never be able to get a model in a dish of a human neurodegenerative disease like this.’ Now, we have them where we can really study and manipulate them, and try to cure them of this horrible disease. The fact that we are able to do this at all still amazes us.” Specifically, the damage caused by HD is due to a mutation in the huntingtin gene (HTT), which leads to the production of an abnormal and toxic version of the huntingtin protein. Although all of the cells in a person with HD contain the mutation, HD mainly targets the medium spiny neurons in the striatum, part of the brain’s basal ganglia that coordinates movement, thought and emotion. The ability to work directly with human medium spiny neurons is the best way, researchers believe, to determine why these specific cells are susceptible to cell stress and degeneration and, in turn, to help find a way to halt progression of HD. Much HD research is conducted in mice. And while mouse models have been helpful in understanding some aspects of the disease, researchers say nothing compares with being able to study actual human neurons affected by HD. For years, scientists have been excited about the prospect of making breakthroughs in curing disease through the use of stem cells, which have the remarkable potential to develop into many different cell types. In the form of embryonic stem cells, they do so naturally during gestation and early life. In recent years, researchers have been able to produce induced pluripotent stem cells (iPSCs), which are adult cells (like the skin cells used in Ross’s experiments) that have been genetically reprogrammed back to the most primitive state. In this state, under the right circumstances, they can then develop into most or all of the 200 cell types in the human body. ### The other members of the research consortium include the University of Wisconsin School of Medicine, Massachusetts General Hospital and Harvard Medical School, the University of California, San Francisco, Cardiff University the Universita degli Studi diMilano and the CHDI Foundation. Primary support for this research came from an American Recovery and Reinvestment Act (ARRA) grant (RC2-NS069422) from the National Institutes of Health’s National Institute of Neurological Disorders and Stroke and a grant from the CHDI Foundation, Inc. Other Johns Hopkins researchers involved in this study include Sergey Akimov, Ph.D.; Nicolas Arbez, Ph.D.; Tarja Juopperi, D.V.M., Ph.D.; Tamara Ratovitski; Jason H. Chiang; Woon Roung Kim; Eka Chighladze, M.S., M.B.A.; Chun Zhong; Georgia Makri; Robert N. Cole; Russell L. Margolis, M.D.; and Guoli Ming, M.D., Ph.D. For more information: http://neuroscience.jhu.edu/ChristopherRoss.php Contact: Stephanie Desmon |
| New compound holds promise for treating Duchenne MD, other inherited diseases Posted: 26 Jun 2012 09:00 PM PDT
Scientists at UCLA have identified a new compound that could treat certain types of genetic disorders in muscles. It is a big first step in what they hope will lead to human clinical trials for Duchenne muscular dystrophy.
Duchenne muscular dystrophy, or DMD, is a degenerative muscle disease that affects boys almost exclusively. It involves the progressive degeneration of voluntary and cardiac muscles, severely limiting the life span of sufferers. In a new study, senior author Carmen Bertoni, an assistant professor in the UCLA Department of Neurology, first author Refik Kayali, a postgraduate fellow in Bertoni’s lab, and their colleagues demonstrate the efficacy of a new compound known as RTC13, which suppresses so-called “nonsense” mutations in a mouse model of DMD. The findings appear in the current online edition of the journal Human Molecular Genetics. “We are excited about these new findings because they represent a major step toward the development of a drug that could potentially treat this devastating disease in humans,” Bertoni said. “We knew that the compounds were effective in cells isolated from the mouse model for DMD, but we did not know how they would behave when administered in a living organism.” Nonsense mutations are generally caused by a single change in DNA that disrupts the normal cascade of events that changes a gene into messenger RNA, then into a protein. The result is a non-functioning protein. Approximately 13 percent of genetic defects known to cause diseases are due to such mutations. In the case of DMD, the “missing” protein is called dystrophin. For the study, Bertoni and Kayali collaborated with the laboratory of Dr. Richard Gatti, a professor of pathology and laboratory medicine and of human genetics at UCLA. Working with the UCLA Molecular Shared Screening Resource facility at the campus’s California NanoSystems Institute, the Gatti lab screened some 35,000 small molecules in the search for new compounds that could ignore nonsense mutations. Two were identified as promising candidates: RTC13 and RTC14. The Bertoni lab tested RTC13 and RTC14 in a mouse model of DMD carrying a nonsense mutation in the dystrophin gene. While RTC14 was not found to be effective, RTC13 was able to restore significant amounts of dystrophin protein, making the compound a promising drug candidate for DMD. When RTC13 was administered to mice for five weeks, the investigators found that the compound partially restored full-length dystrophin, which resulted in a significant improvement in muscle strength. The loss of muscle strength is a hallmark of DMD. The researchers also compared the level of dystrophin achieved to the levels seen with another experimental compound, PTC124, which has proved disappointing in clinical trials; RTC13 was found to be more effective in promoting dystrophin expression. Just as important, Bertoni noted, the study found that RTC13 was well tolerated in animals, which suggests it may also be safe to use in humans. The next step in the research is to test whether an oral formulation of the compound would be effective in achieving therapeutically relevant amounts of dystrophin protein. If so, planning can then begin for clinical testing in patients and for expanding these studies to other diseases that may benefit from this new drug. ### Other study authors included Jin-Mo Ku, Gregory Khitrov, Michael E. Jung and Olga Prikhodko, all from UCLA. The researchers report no conflicts of interest. The work has been supported in large part by the Muscular Dystrophy Association (MDA) and, more recently, by the National Institutes of Health. The UCLA Department of Neurology, with over 100 faculty members, encompasses more than 20 disease-related research programs, along with large clinical and teaching programs. These programs cover brain-mapping and neuroimaging, movement disorders, Alzheimer’s disease, multiple sclerosis, neurogenetics, nerve and muscle disorders, epilepsy, neuro-oncology, neurotology, neuropsychology, headaches and migraines, neurorehabilitation, and neurovascular disorders. The department ranks in the top two among its peers nationwide in National Institutes of Health funding. For more news, visit the UCLA Newsroom and follow us on Twitter. Contact: Mark Wheeler |
| Dietary fiber alters gut bacteria, supports gastrointestinal health Posted: 26 Jun 2012 09:00 PM PDT A University of Illinois study shows that dietary fiber promotes a shift in the gut toward different types of beneficial bacteria. And the microbes that live in the gut, scientists now believe, can support a healthy gastrointestinal tract as well as affect our susceptibility to conditions as varied as type 2 diabetes, obesity, inflammatory bowel disease, colon cancer, and autoimmune disorders such as rheumatoid arthritis.
As these microbes ferment fiber in the intestine, short-chain fatty acids and other metabolites are produced, resulting in many health benefits for the host, said Kelly Swanson, a U of I professor of animal sciences. “When we understand what kinds of fiber best nurture these health-promoting bacteria, we should be able to modify imbalances to support and improve gastrointestinal health,” he said. This research suggests that fiber is good for more than laxation, which means helping food move through the intestines, he added. “Unfortunately, people eat only about half of the 30 to 35 grams of daily fiber that is recommended. To achieve these health benefits, consumers should read nutrition labels and choose foods that have high fiber content,” said Swanson. In the placebo-controlled, double-blind intervention study, 20 healthy men with an average fiber intake of 14 grams a day were given snack bars to supplement their diet. The control group received bars that contained no fiber; a second group ate bars that contained 21 grams of polydextrose, which is a common fiber food additive; and a third group received bars with 21 grams of soluble corn fiber. On days 16-21, fecal samples were collected from the participants, and researchers used the microbial DNA they obtained to identify which bacteria were present. DNA was then subjected to 454 pyrosequencing, a “fingerprinting” technique that provides a snapshot of all the bacterial types present. Both types of fiber affected the abundance of bacteria at the phyla, genus, and species level. When soluble corn fiber was consumed, Lactobacillus, often used as a probiotic for its beneficial effects on the gut, increased. Faecalibacterium populations rose in the groups consuming both types of fiber. According to Swanson, the shifts in bacteria seen in this study?which occurred when more and differing types of fiber were consumed?were the opposite of what you would find in a person who has poor gastrointestinal health. That leads him to believe that there are new possibilities for using pre- and probiotics to promote intestinal health. “For example, one type of bacteria that thrived as a result of the types of fiber fed in this study is inherently anti-inflammatory, and their growth could be stimulated by using prebiotics, foods that promote the bacteria’s growth, or probiotics, foods that contain the live microorganism,” he said. ### The study will appear in the July 2012 issue of the Journal of Nutrition and is available pre-publication online at http://www.ncbi.nlm.nih.gov/pubmed/22649263. Co-authors are Seema Hooda, Brittany M. Vester Boler, Mariana C. Rossoni Serao, and George C. Fahey Jr., all of the U of I Department of Animal Sciences; Jennifer M. Brulc, Michael A. Staeger, and Thomas W. Boileau, all of the General Mills, Inc., Bell Institute of Health and Nutrition; and Scot E. Dowd of MR DNA Molecular Research LP, Shallowater, TX. Funding was provided in part by General Mills. Contact: Phyllis Picklesimer |
| Mayo Clinic uses new approach to reverse multiple sclerosis in mice models Posted: 26 Jun 2012 09:00 PM PDT Mayo Clinic researchers have successfully used smaller, folded DNA molecules to stimulate regeneration and repair of nerve coatings in mice that mimic multiple sclerosis (MS). They say the finding, published today in the journal PLoS ONE, suggests new possible therapies for MS patients.
“The problem has been to find a way to encourage the nervous system to regenerate its own myelin (the coating on the nerves) so nerve cells can recover from an MS attack,” says L. James Maher III, Ph.D., Mayo Clinic biochemist and senior author on the paper. “We show here that these small molecules, called aptamers, can stimulate repair in the mice we are studying.” More than 200,000 people have multiple sclerosis. There is no cure and no effective therapy to stop progression or repair damage to the myelin sheath that surrounds and protects the nerves. Without that protection, nerve fibers will be damaged, leading to declining mobility and cognitive function, and other debilitating complications. MS researchers, including Mayo neurologist Moses Rodriguez, M.D., a co-author on this paper, have focused on monoclonal antibodies in mice to stimulate myelin repair. The Rodriguez and Maher teams, working together, have determined that the aptamers are not only effective, but they are easy and cheap to synthesize — an important point for drug developers. They also are stable and not likely to cause an immune response. This new approach must be validated in other mouse models to see if it might be a candidate for human clinical trials. The monoclonal antibodies used in earlier research are large and complex, but were shown to promote both cell signaling and remyelination of central nervous system lesions in mice. The aptamers used in this study are less than one-tenth the size of antibodies and are single-strands of DNA containing only 40 nucleotide units. ### The research was supported by Mayo Clinic and the National Multiple Sclerosis Society. Co-authors include Branislav Nastasijevic, Brent Wright, Ph.D., John Smestad, and Arthur Warrington, Ph.D., all of Mayo Clinic. About Mayo Clinic
Mayo Clinic is a nonprofit worldwide leader in medical care, research and education for people from all walks of life. For more information, visit http://www.mayoclinic.org/about and www.mayoclinic.org/news
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| New animal model for rheumatoid arthritis Posted: 26 Jun 2012 09:00 PM PDT
Researchers at Northwestern University Feinberg School of Medicine have created the first animal model that spontaneously develops rheumatoid arthritis (RA) and is predisposed towards atherosclerosis, or hardening of the arteries.
This model is considered of critical importance because patients with RA are at increased risk for heart attack and other premature cardiovascular events, but scientists don’t know why. “Generally, people with RA die because of cardiovascular disease,” said Harris Perlman, associate professor of rheumatology at Feinberg, who is corresponding author on the paper. “This new model will allow us to examine the systemic influence of inflammatory arthritis on the development of heart disease.” RA is a chronic, inflammatory disease that causes pain, swelling, stiffness and loss of function in joints. The disease can affect any joint but is common in the wrist and fingers. Approximately 1.3 million people live with RA, and more women than men have the disease, which often starts between ages 25 and 55. Perlman’s team developed a specialized mouse model with RA, then fed the animals a “high-fat, Western-type” diet. “As we see in patient populations, the RA-affected mice spontaneously developed atherosclerosis,” he said. Mice without RA who were fed the same diet did not develop atherosclerosis. Next, Harris’ team treated the affected animals with Enbrel®, a common first-line therapeutic for joint inflammation in humans. Following an eight-week course of treatment, the occurrence of atherosclerosis decreased by 50 percent in the animal model. The findings are published online in Annals of the Rheumatic Diseases. “This unique animal model will allow us to address a number of important questions regarding the connections between RA and cardiovascular disease,” said Perlman. “The most pressing question will be to explore how drugs that treat RA inhibit cardiovascular disease. What’s the mechanism at work? We also want to understand how cardiovascular disease and RA work together in the body.” Perlman says the findings were made possible by a series of collaborations at Northwestern University involving the divisions of rheumatology and cardiology at Feinberg, as well as the Center for Advanced Molecular Imaging (CAMI) on the Evanston campus. ### This work was supported by grants Driskill Fellow Scholarship award, NIH grant (AR07611) and NIH LRP to Shawn Rose, HHMI (57006753) to C. Shad Thaxton, NIH grants (HL051387 and HL108795) to Douglas Vaughan, NIH grants (EB005866 and CA151880) to Thomas Meade, and NIH grants (AR050250, AR054796,AI092490, and HL108795) and Funds provided by Northwestern University Feinberg School of Medicine to Harris Perlman. Northwestern University investigators Shawn Rose, Mesut Eren, Sheila Murphy, Heng Zhang, C. Shad Thaxton, Jamie Chowaniec, Emily A. Waters, Thomas Meade, and Douglas Vaughan were co-authors on the study. Contact: Marla Paul |
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