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.
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.
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.
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.
European badgers can make journeys of more than 20 kilometers – distances longer than previously thought – researchers have found. The study, published online on March 6, 2014 in the British Ecological Society's Journal of Animal Ecology, could help scientists design more effective interventions to reduce the spread of bovine tuberculosis (bTB) between badger populations, something that is essential if transmission to cattle is to be controlled. Animal movement is a key part of population ecology, helping us to understand how species use their environment and maintain viable populations. In many territorial species, most movements occur within a home range. Occasionally, however, individuals make long-distance movements. Long-distance movements are important: they ensure that populations mix and do not inbreed, but they can also spread infection between populations. They are also rare, so long-distance movements are difficult to study and require large, long-term studies. Because of their importance as a reservoir for bTB, badgers are a well-studied species. While we know a great deal about how badgers move in and around their home territories, very little is known about rare long-distance movements and nothing about how often badgers travel these long distances. To answer these questions, scientists from Ireland and Canada studied badger movements for four years across a 755 square kilometer area of County Kilkenny in the Republic of Ireland – the largest spatial-scale badger study of its type ever conducted in Europe. Dr. Andrew Byrne of University College Dublin, who led the research while at University College Cork, said: “To study these longer-distance movements, a correspondingly large study area is required.
It's by now well established that obesity is a major risk factor for diabetes. But what exactly is it about extra body fat that leads to insulin resistance and blood glucose elevation, the hallmarks of diabetes? Over the past several years, Beth Israel Deaconess Medical Center (BIDMC) endocrinologist Barbara Kahn, M.D., has developed a large body of research suggesting that a molecule called retinol binding protein 4 (RBP4) (image) plays a key role in the process. Dr. Kahn's lab was the first to show that elevated levels of RBP4 – previously known only for its role as a transport protein for Vitamin A – led to the development of insulin resistance in animal models. Additional work revealed parallel results in human blood samples: obese, insulin-resistant individuals had high RBP4 levels and lean, insulin-sensitive people had low RBP4 levels. Furthermore, people with genetic changes in RBP4 that resulted in high blood levels of the protein had an elevated risk of developing diabetes. Now, Dr. Kahn and her colleagues explain the mechanism by which RBP4 contributes to increased risk of diabetes. In a study that appears online in the March 4, 2014 issue of the journal Cell Metabolism, the investigators describe how the protein sets in motion a complex interplay between two branches of the body's immune system, leading to chronic fat tissue inflammation and, ultimately, insulin resistance. "Although the inflammatory response is a key part of our immune system and an important means of protection and tissue repair in response to infection or injury, under certain conditions of metabolic dysfunction, this response is activated even in the absence of foreign pathogens," explains Dr.
A team of University of Notre Dame researchers led by Drs. Mayland Chang and Shahriar Mobashery has discovered a new class of antibiotics to fight bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) and other drug-resistant bacteria that threaten public health. The new research is published in the Journal of the American Chemical Society in an article titled "Discovery of a New Class of Non-Beta-Lactam Inhibitors of Penicillin-Binding Proteins with Gram-Positive Antibacterial Activity." The new class, called oxadiazoles, was discovered by in silico (by computer) screening and has shown promise in the treatment of MRSA in mouse models of infection. Researchers who screened 1.2 million compounds found that the oxadiazole inhibits a penicillin-binding protein, PBP2a, and the biosynthesis of the cell wall that enables MRSA to resist other drugs. The oxadiazoles are also effective when taken orally. This is an important feature as there is only one marketed antibiotic for MRSA that can be taken orally. MRSA has become a global public-health problem since the 1960s because of its resistance to antibiotics. In the United States alone, 278,000 people are hospitalized and 19,000 die each year from infections caused by MRSA. Only three drugs currently are effective treatments, and resistance to each of those drugs already exists. The researchers have been seeking a solution to MRSA for years. "Professor Mobashery has been working on the mechanisms of resistance in MRSA for a very long time," Dr. Chang said. "As we understand what the mechanisms are, we can devise strategies to develop compounds against MRSA." "Mayland Chang and Shahriar Mobashery's discovery of a class of compounds that combat drug resistant bacteria such as MRSA could save thousands of lives around the world.
Sangamo BioSciences, Inc. (Nasdaq: SGMO), announced on March 6, 2014 the presentation of data from its SB-728-T program to develop a “functional cure” for HIV/AIDS at the Conference on Retroviruses and Opportunistic Infections (CROI 2014). The conference was held in Boston from March 3 to 6, 2014. Data from an earlier Phase 1 clinical study in this program were also published in the March 6, 2014 issue of the New England Journal of Medicine(NEJM) (see BioQuick story below). "The achievement of over 7 months of ongoing functional control of viral load without antiretroviral therapy and the progress that we are making in understanding how to best deploy this novel therapy are very exciting," commented Gary Blick, M.D., AAHIVS, Medical & Research Director, CIRCLE CARE Center, who presented the data at CROI and is an investigator on both studies that were reported at the meeting. "The data that have been generated over the course of the clinical investigation of SB-728-T demonstrate immune reconstitution, enhanced survival of the zinc finger nuclease-modified T-cells in the presence of the virus, and associated reductions in viral load and the levels of viral reservoir, all of which are necessary to provide functional control of the virus." At CROI, data were reported from a Phase 1 /2 clinical trial, SB-728-1101, designed to evaluate the effect of increasing doses of Cytoxan preconditioning as a method to increase the numbers of circulating T-cells, including cells that were zinc finger nuclease (ZFN) modified at the CCR5 gene (SB-728-T). The data demonstrate that increasing doses of Cytoxan preconditioning prior to a single infusion of SB-728-T led to a dose-dependent increase in both engraftment of CCR5-modified cells and notable increases in total CD4 cells above the baseline.
Sangamo BioSciences, Inc. (Nasdaq: SGMO) announced on March 5, 2014 the publication in the March 6, 2014 issue of the New England Journal of Medicine of the first clinical study of Sangamo's proprietary zinc finger nuclease (ZFN)-based genome editing technology in humans. Data from the study, carried out in HIV-positive subjects, demonstrate that the T-cell genome can be safely engineered to mimic a naturally occurring mutation that provides resistance to HIV infection. ZFN-modified T-cells are well tolerated when reinfused and treatment is associated with decreased viral loads (VLs) in several subjects who were taken off their antiretroviral therapy (ART), including one whose viral load became undetectable. The study demonstrates the feasibility of this novel genome editing approach to achieve functional control of HIV. Additional data on the ongoing SB-728-T ongoing clinical trials in HIV will be presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2014), which is taking place in Boston, March 3-6, 2014. "We have used Sangamo's ZFN technology to safely genetically engineer an HIV-infected individual's own T-cells and to make those cells resistant to infection by the virus," said Carl June, M.D., Richard W. Vague Professor in Immunotherapy in the department of Pathology and Laboratory Medicine at the Perelman School of Medicine at the University of Pennsylvania, and a senior author of the paper. "This study demonstrates that ZFN-modified cells can be safely administered back to the individual; are able to persist and circulate throughout the body to key reservoirs of HIV infection; and show preferential survival over unmodified cells when antiviral drugs are withdrawn, potentially keeping the virus under control without the use of drugs.
New findings reveal how a mutation that causes neurodegeneration alters the shape of DNA, making cells more vulnerable to stress and more likely to die. The particular mutation, in the C9orf72 gene, is the most common cause for amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease), and frontotemporal degeneration (FTD), the second most common type of dementia in people under 65. This new research by Jiou Wang, Ph.D., and his colleagues at Johns Hopkins University (JHU) was published online on March 5, 2014 in Natureand was partially funded by the National Institutes of Health's National Institute of Neurological Disorders and Stroke (NINDS). In ALS, the muscle-activating neurons in the spinal cord die, eventually causing paralysis. In FTD, neurons in particular brain areas die leading to progressive loss of cognitive abilities. The mutation may also be associated with Alzheimer's and Huntington's diseases. The normal C9orf72 gene contains a section of repeating bases; in most people, this sequence is repeated two to 25 times. In contrast, the mutation associated with ALS and FTD can result in up to tens of thousands of repeats of this section. Using sophisticated molecular techniques, Dr. Wang and his team showed that the C9orf72 mutation causes changes in the three-dimensional shape of DNA. DNA is normally shaped like a twisted ladder. However, the repeating sequences can fold into so-called G-quadruplexes, stacks of square-shaped molecules known as G-quartets. "This structure has been described as a square building with each floor representing one G-quartet, normally two to four stories high," said Dr. Wang, senior author of the Nature article. The team’s results also showed that C9orf72 mutated DNA has profound effects on how the genetic message is processed in the cell.