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Archive - Mar 2014

Date

March 11th

Experimental Drugs for Hepatitis C Offer Hope for Effective Treatment, Fewer Side Effects

Patrizia Cazzaniga had heard the horror stories about early treatments for hepatitis C – multiple daily pills and weekly shots for up to a year, side effects that could be debilitating, and a cure rate of only about 40 percent. According to a March 11, 2014 press release from the University of Texas (UT) Southwestern Medical Center, after a shorter and less intensive treatment with experimental drugs at the UT Southwestern Medical Center that ended in October, Mrs. Cazzaniga is now virus-free three months past treatment. She’s thrilled. “If you don’t get treatment, you can get cancer or cirrhosis. That scared me. Now I feel great, my energy has come back, and I don’t have trouble with my stomach anymore,” said Mrs. Cazzaniga, 57, who took part in one of 10 current clinical trials testing new hepatitis drugs at UT Southwestern. “These new drugs are much more potent and effective,” said Dr. William M. Lee, Professor of Internal Medicine at UT Southwestern and local site investigator for these ongoing national and international drug trials. In the U.S., the Centers for Disease Control and Prevention (CDC) estimates that 4.1 million people carry the hepatitis C virus, with 3.2 million of them chronically infected. Further, CDC data show that about 15,000 Americans infected with the virus die annually from liver disease. About 75 percent of those infected do not know they have hepatitis C, because symptoms may not occur until later stages of the disease. For years, the standard treatment was six ribavirin capsules daily and weekly peginterferon shots. The treatment period was long – nearly a year – and side effects could include body aches, fatigue, headaches, anxiety, or depression.

Researchers Make Insulin-Producing Cells from Gut Cells

Destruction of insulin-producing beta cells in the pancreas is at the heart of type 1 and type 2 diabetes. "We are looking for ways to make new beta cells for these patients to one day replace daily insulin injections," says Ben Stanger, M.D., Ph.D., assistant professor of Medicine in the Division of Gastroenterology, Perelman School of Medicine at the University of Pennsylvania. Transplanting islet cells to restore normal blood sugar levels in patients with severe type 1 diabetes is one approach to treating the disease, and using stem cells to create beta cells is another area of investigation. However, both of these strategies have limitations: transplantable islet cells are in short supply, and stem cell-based approaches have a long way to go before they reach the clinic. "It's a powerful idea that if you have the right combination of transcription factors you can make any cell into any other cell. It's cellular alchemy," comments Dr. Stanger. New research from Dr. Stanger and postdoctoral fellow Yi-Ju Chen, Ph.D., together with a host of colleagues, reported online on March 6, 2014 in an open-access article in Cell Reports, describes how introducing three proteins that control the regulation of DNA in the nucleus -- called transcription factors -- into an immune-deficient mouse turned a specific group of cells in the gut lining into beta-like cells, raising the prospect of using differentiated pancreatic cells as a source for new beta cells. In 2008, the lab of Dr. Stanger's postdoctoral mentor introduced the three beta-cell reprogramming factors -- Pdx1 (P), MafA (M), and Ngn3 (N) -- collectively called PMN – into the acinar cells of the pancreas. Remarkably, this manipulation caused the cells to take on some structural and physiological features of beta cells.

Cancer Cells Take Direct Route Not Random Walk When Metastasizing

Because of results seen in flat lab dishes, biologists have believed that cancers cells move through the body in a slow, aimless fashion, resembling an intoxicated person who cannot walk three steps in a straight line. This pattern, called a random walk, may hold true for cells traveling across two-dimensional lab containers, but Johns Hopkins researchers have discovered that for cells moving through three-dimensional spaces within the body, the “random walk” model doesn’t hold true. This finding, reported in the March 4, 2014 online Early Edition of PNAS, is important because it should lead to more accurate results for scientists studying how cancer spreads through the body, often leading to a grim prognosis. To address this dimensional disagreement, the study’s authors have produced a new mathematical formula that they say better reflects the behavior of cells migrating through 3D environments. The research was supervised by Dr. Denis Wirtz, the university’s Theophilus H. Smoot Professor, with appointments in the departments of Chemical and Biomolecular Engineering, Pathology and Oncology within Johns Hopkins’ Whiting School of Engineering and School of Medicine. Dr. Wirtz said the discovery reinforces the current shift toward studying how cells move within three dimensions. His lab team has conducted earlier studies showing that that cells in 2D and 3D environments behave differently, which affects how cancer migrates within the body. “Cancer cells that break away from a primary tumor will seek out blood vessels and lymph nodes to escape and metastasize to distant organs,” Dr. Wirtz said. “For a long time, researchers have believed that these cells make their way to these blood vessels through random walks. In this study, we found out that they do not.

Gene Therapy for Lysosomal Storage Disease

Several young children suffering from a severe degenerative genetic disease received injections of therapeutic genes packaged within a noninfectious viral delivery vector. Safety, tolerability, and efficacy results from this early stage clinical trial are reported in Human Gene Therapy. Dr. Marc Tardieu, Université Paris-Sud and INSERM, and a team of international researchers administered the adeno-associated viral (AAV) vector carrying a normal copy of the N-sulfoglycosamine sulfohydrolase (SGSH) gene into the brains of four children affected by mucopolysaccharidosis type IIIA (MPSIIIA), an inherited lysosomal storage disease in which the SGSH gene is defective. The AAV vector also delivered a sulfatase-modifying factor (SUMF1), needed to activate the SGSH protein. In addition to measures of toxicity, adverse events, and tolerability, the researchers evaluated the children for brain shrinkage (a characteristic of MPSIIIA) and for changes in behavior, attention, sleep, and cognitive benefit. They describe their findings in the article "Intracerebral administration of AAV rh.10 carrying human SGSH and SUMF1 cDNAs in children with MPSIIIA disease: results of a phase I/II trial." "This is an important new approach for treating CNS manifestations of lysosomal storage diseases that could be applied across a wide array of disorders," says James M. Wilson, M.D., Ph.D., Editor-in-Chief of Human Gene Therapy, and Director of the Gene Therapy Program, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia.

Potential New Heart Attack Drug with Minimal or No Side Effects

Melbourne, Australia scientists are a step closer to creating a new drug to stop a heart attack in its tracks and reduce the damage caused, without any side effects. The Monash University research, published online in the early edition of PNAS, offers new hope to thousands of people who experience heart attacks and heart failure – one of the major causes of death worldwide. Professors Arthur Christopoulos and Peter Scammells from the Monash Institute of Pharmaceutical Sciences (MIPS) led a team of scientists combining molecular pharmacology and medicinal chemistry to reveal new insights into a specific protein belonging to the family of G-protein-coupled receptors (GPCRs). After successfully combining two molecules, the researchers are a step closer to creating a brand new class of drug that is more targeted and could possess minimal side effects. GPCRs play a role in virtually every biological process and most diseases, including, cardiovascular disease, obesity and diabetes, neuropsychiatric disorders, inflammation, and cancer. Almost half of all current medications available use GPCRs to achieve their therapeutic effect. Current GPCR drugs work either by fully activating or completely blocking receptors, treating the protein like a simple “on-off” switch. This new research discovered alternative recognition sites on GPCRs that can be targeted by drugs to fine-tune the behavior of the protein, basically converting the “on-off” switch into a “dimmer switch”. Professor Christopoulos said it was this insight that enabled the new breakthrough. “When a heart attack strikes, heart cells die because of a lack of oxygen and nutrients.

New Tool to Study Kinase Activities at Heart of Many Diseases and Metastasis

Researchers at the University of North Carolina (UNC) School of Medicine have devised a new biochemical technique that will allow them and other scientists to delve much more deeply than ever before into the specific cellular circuitry that keeps us healthy or causes disease. The method – developed in the lab of Klaus Hahn, Ph.D., and described online on March 9, 2014 in the journal Nature Chemical Biology – helps researchers study how specific proteins called kinases interact to trigger a specific cellular behavior, such as how a cell moves. These kinase interactions are extraordinarily complex, and their interactions remain largely unknown. But researchers do know that kinases are crucial operators in disease. "I dare you to find a disease in which kinases are not involved," said Dr. Hahn, senior author of the study and the Thurman Distinguished Professor of Pharmacology. "These kinase processes have been very difficult to fully understand, but we all know they're very important." For years, scientists have been able to tweak a kinase to see what would happen – such as causing cell death or cell movement or cellular signaling. But these experiments can only scratch the surface when it comes to understanding the cascade of kinase interactions that lead to a cellular behavior. Nor have these experiments been able to show the timing of rapid events. That's important, Dr. Hahn said, because when a protein is activated has a lot to do with how the cell will respond. Drug developers haven't been able to take this into account, which is likely one reason why some drugs that target proteins don't work as well as scientists had hoped.

March 9th

New Blood Test Identifies Healthy Individuals at Risk of Alzheimer’s in Three Years

Researchers have discovered and validated a blood test that can predict with greater than 90 percent accuracy if a healthy person will develop mild cognitive impairment or Alzheimer's disease within three years. Described in a Nature Medicine article published online on March 9, 2014, the study heralds the potential for developing treatment strategies for Alzheimer's at an earlier stage, when therapy would be more effective at slowing or preventing onset of symptoms. It is the first known published report of blood-based biomarkers for preclinical Alzheimer's. The test identifies 10 lipids, or fats, in the blood that predict disease onset. It could be ready for use in clinical studies in as few as two years and, researchers say, other diagnostic uses are possible. "Our novel blood test offers the potential to identify people at risk for progressive cognitive decline and can change how patients, their families, and treating physicians plan for and manage the disorder," says the study's corresponding author Howard J. Federoff, M.D., Ph.D., professor of neurology and executive vice president for health sciences at Georgetown University Medical Center. There is no cure or effective treatment for Alzheimer's. Worldwide, approximately 35.6 million individuals have the disease and, according to the World Health Organization, the number will double every 20 years to 115.4 million people with Alzheimer's by 2050. Dr. Federoff explains there have been many efforts to develop drugs to slow or reverse the progression of Alzheimer's disease, but all of them have failed. He says one reason may be the drugs were evaluated too late in the disease process. "The preclinical state of the disease offers a window of opportunity for timely disease-modifying intervention," Dr. Federoff says.

Craig Venter Co-Founds Company Intended to Be Largest Human Sequencing Operation in World

Human Longevity Inc. (HLI), a genomics and cell therapy-based diagnostic and therapeutic company focused on extending the healthy, high-performance human life span, was announced on March 4, 2014 by co-founders J. Craig Venter, Ph.D., Robert Hariri, M.D., Ph.D., and Peter H. Diamandis, M.D. The company, headquartered in San Diego, California, is being capitalized with an initial $70 million in investor funding. HLI’s funding is being used to build the largest human sequencing operation in the world to compile the most comprehensive and complete human genotype, microbiome, and phenotype database available to tackle the diseases associated with aging-related human biological decline. HLI is also leading the development of cell-based therapeutics to address age-related decline in endogenous stem cell function. Revenue streams will be derived from database licensing to pharmaceutical, biotechnology, and academic organizations, sequencing, and development of advanced diagnostics and therapeutics. “Using the combined power of our core areas of expertise—genomics, informatics, and stem cell therapies, we are tackling one of the greatest medical/scientific and societal challenges—aging and aging related diseases,” said Dr. Venter. “HLI is going to change the way medicine is practiced by helping to shift to a more preventive, genomic-based medicine model which we believe will lower healthcare costs. Our goal is not necessarily lengthening life, but extending a healthier, high-performing, more productive life span.” HLI has initially purchased two Illumina HiSeq X Ten Sequencing Systems (with the option to acquire three additional systems) to sequence up to 40,000 human genomes per year, with plans to rapidly scale up to 100,000 human genomes per year.

Anti-Psychotic Medications Offer Unexpected Hope in Glioblastoma Battle

Researchers at the University of California (UC), San Diego School of Medicine, together with colleagues, have discovered that FDA-approved anti-psychotic drugs possess tumor-killing activity against the most aggressive form of primary brain cancer, glioblastoma. The finding was published online on March 7, 2014 in Oncotarget. The team of scientists, led by principal investigator Clark C. Chen, M.D., Ph.D., vice-chairman, UC San Diego, School of Medicine, division of neurosurgery, used a technology platform called shRNA to test how each gene in the human genome contributed to glioblastoma growth. The discovery that led to the shRNA technology won the Nobel Prize in Physiology/Medicine in 2006. "ShRNAs are invaluable tools in the study of what genes do. They function like molecular erasers," said Dr. Chen. "We can design these 'erasers' against every gene in the human genome. These shRNAs can then be packaged into viruses and introduced into cancer cells. If a gene is required for glioblastoma growth and the shRNA erases the function of that gene, then the cancer cell will either stop growing or die." Dr. Chen said that one surprising finding is that many genes required for glioblastoma growth are also required for dopamine receptor function. Dopamine is a small molecule that is released by nerve cells and binds to the dopamine receptor in surrounding nerve cells, enabling cell communication. Abnormal dopamine regulation is associated with Parkinson's disease, schizophrenia, and attention deficit hyperactivity disorder. Because of the importance of dopamine in these diseases, drugs have been developed to neutralize the effect of dopamine, called dopamine antagonists. Following clues unveiled by their shRNA study, Dr.

Test for Persistent Lyme Infection Uses Live Ticks

In a first-of-its-kind study for Lyme disease, researchers have used live, disease-free ticks to see if Lyme disease bacteria can be detected in people who continue to experience symptoms such as fatigue or arthritis after completing antibiotic therapy. The technique, called xenodiagnosis, attempts to find evidence of a disease-causing microbe indirectly, through use of the natural disease-carrier—in this case, ticks. It was well tolerated by the volunteers, but investigators could not find evidence of Lyme disease bacteria in most of the cases where enough ticks were collected to make testing possible. Larger studies are needed, the scientists say, to determine the significance of positive xenodiagnosis results in cases where Lyme disease symptoms persist following antibiotic therapy. Adriana Marques, M.D., of the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and Linden Hu, M.D., of Tufts Medical Center, Boston, led the pilot study. Findings were published online on February 11, 2014 in Clinical Infectious Diseases. The most common tick-borne illness in the United States, Lyme disease is caused by Borrelia burgdorferi bacteria that are transmitted to people by ticks of the Ixodes genus. "Most cases of Lyme disease are cured by antibiotics, but some patients continue to experience symptoms despite the absence of detectable Lyme bacteria," said NIAID Director Anthony S. Fauci, M.D. "This poses a mystery that requires continued research into new or improved ways to diagnose Lyme disease and determine the cause of unresolved symptoms." "Xenodiagnosis using ticks to detect B. burgdorferi has been used previously in animal studies, but this is the first time it has been tried in people," said Dr. Marques.