Drug shows promise as single-dose cure and as preventive treatment for malaria, researchers find

Researchers at UT Southwestern Medical Center and in Australia have shown that a drug currently in testing shows potential to cure malaria in a single dose and offers promise as a preventive treatment as well.


The new drug – DSM265 – kills drug-resistant malaria parasites in the blood and liver by targeting their ability to replicate. Malaria is a highly infectious, mosquito-transmitted disease that kills nearly 600,000 people worldwide each year, mostly children under 5 years old living in sub-Saharan Africa. Nearly 200 million cases of malaria are reported annually, and about 3 billion people are at risk of malaria in 97 countries.


“DSM265 could be among the first single-dose cures for malaria, and would be used in partnership with another drug,” said lead author Dr. Margaret Phillips, Professor of Pharmacology at UT Southwestern. “The drug also could potentially be developed as a once-weekly preventive.”


The research team included UT Southwestern, the Monash Institute of Pharmaceutical Sciences in Australia, the University of Washington, and the not-for-profit Medicines for Malaria Venture (MMV). The study was published in Science Translational Medicine.


Researchers determined that the compound DSM265 kills the malaria parasite Plasmodium in both liver and blood stages of infection. Further, the compound was shown to be well tolerated and effective in preclinical models.


Currently, the frontline anti-malarial treatments are artemisinin-based combination therapies, or ACTs, which are credited with helping to reduce the malaria burden. However, malaria strains resistant to ACTs have recently been reported in Thailand, Cambodia, Vietnam, Myanmar, and Laos.


“The problem is we’re starting to see more drug resistance, and this is what’s taken out every anti-malarial drug we’ve had,” said Dr. Phillips, who holds the Beatrice and Miguel Elias Distinguished Chair in Biomedical Science, and the Carolyn R. Bacon Professorship in Medical Science and Education. “The parasite is very good at adapting and becoming resistant to drugs − this is inevitable. What we can do is deliver new medicines with new modes of action and safeguard the longevity of the anti-malarial through use in combination as long as possible.”


In order to combat drug resistance, DSM265 likely would be partnered with another new drug and used as a one-dose combination therapy. Another option is to develop DSM265 as a once-weekly preventive for individuals traveling to malaria-endemic regions or for people living in areas where malaria infections are primarily seasonal and human immunity is low. Either scenario is still several years away, pending the outcome of current and future trials, said Dr. Phillips.


DSM265 targets the ability of the parasite to synthesize the nucleotide precursors required for synthesis of DNA and RNA, said Dr. Phillips.


The study concluded that DSM265 appeared to be safely tolerated in non-human tests and established optimal dosing levels and length of drug effectiveness in preclinical models to estimate dosing for humans, paving the way for clinical trials. The first clinical trial was a safety study in Australia, followed by an ongoing efficacy study in Peru to evaluate the ability to treat patients with malaria. Additional human studies are planned, including one to test the drug as a preventive medicine. UT Southwestern is assisting in an advisory capacity in these studies and is providing support with biomarker assays.


Work on DSM265 began in Dr. Phillips’ lab. In 2008, her research team identified an inhibitor of an enzyme that the malaria parasite requires for survival. This enzyme, dihydroorotate dehydrogenase (DHODH), enables the parasite to replicate and spread during infection of humans. The lead drug compound discovered during high-throughput tests at UT Southwestern’s core screening laboratory was then refined to DSM265 in partnership with Dr. Susan Charman at Monash University, the study’s senior author; Dr. Pradipsinh Rathod at the University of Washington; and MMV-affiliated researchers.


DSM265 is the first DHODH inhibitor to reach clinical development for treatment of malaria.


Drs. Phillips, Charman, Rathod, and Dr. Jeremy Burrows of MMV are named as inventors in a pending patent application covering DSM265 and related compounds. The drug has been licensed to MMV, which is leading the clinical trial in Peru. MMV works with institutions and drug companies worldwide to further research and development of new malaria treatments. DSM265 is one of several potential anti-malarial drugs now in various stages of development in collaboration with MMV.


Other UT Southwestern researchers involved in this study included Farah El Mazouni, a research scientist in Pharmacology; Dr. Diana Tomchick, Professor of Biophysics and Biochemistry, and Dr. Xiaoyi Deng, Instructor of Pharmacology.


UT Southwestern collaborated on this study with researchers from the University of Washington, Massachusetts Institute of Technology, Columbia University Medical Center, SUNY Upstate Medical University, SRI International, and the National Institutes for Allergy and Infectious Diseases in the United States; MMV, and the Swiss Tropical and Public Health Institute in Switzerland; Monash and Griffith University in Australia; Biomedical Primate Research Center, and TropIQ Health Sciences of The Netherlands; the Imperial College of Science, Technology and Medicine in the United Kingdom; and GlaxoSmithKline divisions in both Spain and the United Kingdom.


The research was funded by MMV, the National Institutes of Health, the Welch Foundation, and the Wellcome Trust. Dr. Phillips and two other authors not affiliated with UT Southwestern are paid consultants for MMV. Other authors hold stock in TropIQ, and another is a paid consultant to Hepregen.




Source: UT Southwestern Medical Center


Published on  16th  July  2015

Walking an Extra Two Minutes Each Hour May Offset Hazards of Sitting Too Long

A new study suggests that engaging in low intensity activities such as standing may not be enough to offset the health hazards of sitting for long periods of time. On the bright side, adding two minutes of walking each hour to your routine just might do the trick. These findings were published in the Clinical Journal of the American Society of Nephrology (CJASN).

U.Va. Research Overturns Basic Beliefs About Atherosclerosis

Doctors’ efforts to battle the dangerous atherosclerotic plaques that build up in our arteries and cause heart attacks and strokes are built on several false beliefs about the fundamental composition and formation of the plaques, new research from the University of Virginia School of Medicine shows.

These new discoveries will force researchers to reassess their approaches to developing treatments and discard some of their basic assumptions about atherosclerosis, commonly known as hardening of the arteries.


“The leading cause of death worldwide is complications of atherosclerosis, and the most common end-stage disease is when an atherosclerotic plaque ruptures. If this occurs in one of your large coronary arteries, it’s a catastrophic event,” said Gary K. Owens of U.Va.’s Robert M. Berne Cardiovascular Research Center. “Once a plaque ruptures, it can induce formation of a large clot that can block blood flow to the downstream regions. This is what causes most heart attacks. The clot can also dislodge and cause a stroke if it lodges in a blood vessel in the brain. As such, understanding what controls the stability of plaques is extremely important.”


Until now, doctors have believed that smooth muscle cells – the cells that help blood vessels contract and dilate – were the good guys in the body’s battle against atherosclerotic plaque. They were thought to migrate from their normal location in the blood vessel wall into the developing atherosclerotic plaque, where they would attempt to wall off the accumulating fats, dying cells and other nasty components of the plaque. The dogma has been that the more smooth muscle cells there are in that wall – particularly in the innermost layer referred to as the “fibrous cap” – the more stable the plaque is and the less danger it poses.


U.Va.’s research reveals those notions are woefully incomplete at best. Scientists have grossly misjudged the number of smooth muscle cells inside the plaques, the work shows, suggesting the cells are not just involved in forming a barrier so much as contributing to the plaque itself.


“We suspected there were a small number of smooth muscle cells we were failing to identify using the typical immunostaining detection methods,” Owens said. “It wasn’t a small number. It was 82 percent. Eighty-two percent of the smooth muscle cells within advanced atherosclerotic lesions cannot be identified using the typical methodology since the lesion cells down-regulate smooth muscle cell markers. As such, we have grossly underestimated how many smooth muscle cells are in the lesion.”


Suddenly, the role of smooth muscle cells is much more complex, much less black-and-white. Are they good or bad? Should treatments try to encourage more? It’s no longer that simple, and the problem is made all the more complicated by the fact that some smooth muscle cells were being misidentified as immune cells called macrophages, while some macrophage-derived cells were masquerading as smooth muscle cells. It’s very confusing, even for scientists, and it has led to what Owens called “complete ambiguity as to which cell is which within the lesion.” (The research also shows other subsets of smooth muscle cells were transitioning to cells resembling stem cells and myofibroblasts.)


Researcher Laura S. Shankman, a Ph.D. student in the Owens lab, was able to overcome the limitations of the traditional methods for detecting smooth muscle cells in the plaque. Her approach was to genetically tag smooth muscle cells early in their development, so she could follow them and their descendants even if they changed their stripes.


“This allowed us to mark smooth muscle cells when we were confident that they were actually smooth muscle cells,” she said. “Then we let the atherosclerosis develop and progress [in mice] in order to see where those cells were later in disease.”


Further, Shankman identified a key gene, Klf4, that appears to regulate these transitions of smooth muscle cells. Remarkably, when she genetically knocked out Klf4 selectively in smooth muscle cells, the atherosclerotic plaques shrank dramatically and exhibited features indicating they were more stable – the ideal therapeutic goal for treating the disease in people. Of major interest, loss of Klf4 in smooth muscle cells did not reduce the number of these cells in lesions, but resulted in them undergoing transitions in their functional properties that appear to be beneficial in disease pathogenesis. That is, it switched them from being “bad” guys to “good” guys.


Taken together, Shankman’s findings raise many critical questions about previous studies built on techniques that failed to assess the composition of the lesions accurately. Moreover, her studies are the first to indicate that therapies targeted at controlling the properties of smooth muscle cells within lesions may be highly effective in treating a disease that is the leading cause of death worldwide.


The discoveries have been outlined in a paper published online by the journal Nature Medicine.



The paper’s authors are Shankman, Delphine Gomez, Olga A. Cherepanova, Morgan Salmon, Gabriel F. Alencar, Ryan M. Haskins, Pamela Swiatlowska, Alexandra A.C. Newman, Elizabeth S. Greene, Adam C. Straub, Brant Isakson, Gwendalyn J. Randolph and Owens.


The work was funded by the National Institutes of Health and the American Heart Association.



Source:   University of Virginia


Published on  9th July 2015



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Distinguishing coincidence from causality: connections in the climate system

Detecting how changes in one spot on Earth – in temperature, rain, wind – are linked to changes in another, far away area is key to assessing climate risks. Scientists now developed a new technique of finding out if one change can cause another change or not, and which regions are important gateways for such teleconnections. They use advanced mathematical tools for an unprecedented analysis of data from thousands of air pressure measurements. The method now published in Nature Communications can be applied to assess geoengineering impacts as well as global effects of local extreme weather events, and can potentially also be applied to the diffusion of disturbances in financial markets, or the human brain.


“Despite the chaos of weather you see a lot of correlations – for instance higher pressure in the East Pacific is often followed by lower pressure in the Indian Monsoon region,” says lead-author Jakob Runge of the Potsdam Institute for Climate Impact Research (PIK). “However, if you take a closer look, you find that many correlations are simply due to another process driving both regions, an important example being the solar cycle. So you use elaborate statistics to reveal such spurious links, find new indirect pathways, and step by step you reconstruct a network more closely representing cause and effect.” The new tool detects where major perturbations entering the climate system have the largest global effect, and via which pathways they are conveyed.


East Pacific, Indonesia, tropical Atlantic most important


The East Pacific, Indonesia and the tropical Atlantic are the regions most important for spreading and transmitting perturbations, the scientists found. One reason is that in these regions particularly huge air masses rise high up in the atmosphere. So for instance warming in the East Pacific can disturb the Indian Monsoon, even though it is thousands of kilometers away. This can put at risk yields on which millions of small farmers and in fact large parts of the population depend.


“How to robustly distinguish coincidence from causality in complex nonlinear systems has long been a riddle,” says Jürgen Kurths, co-author and head of PIK’s Research Domain Transdisciplinary Concepts and Methods. “Conventional approaches, based on pairwise association measures, in some cases showed good results. Yet these methods are rather limited. You can compare it to multiple organ failure in the human body – a real puzzle for the doctors. We’re glad that we can now present a new approach to understanding the connections, which is the basis for ideally making the whole system more resilient.”




Source: Potsdam Institute for Climate Impact Research (PIK)


Published on  8th  October  2015

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