BreakThrough Digest Medical News |
- Unique peptide could treat cancers, neurological disorders, and infectious diseases
- UAB researchers cure type 1 diabetes in dogs
- Compound developed by scientists protects heart cells during and after attack
- Scientists find key to growth of ‘bad’ bacteria in inflammatory bowel disease
| Unique peptide could treat cancers, neurological disorders, and infectious diseases Posted: 06 Feb 2013 09:00 PM PST UT Southwestern Medical Center scientists have synthesized a peptide that shows potential for pharmaceutical development into agents for treating infections, neurodegenerative disorders, and cancer through an ability to induce a cell-recycling process called autophagy.
Autophagy is a fundamental recycling process in which intracellular enzymes digest unneeded and broken parts of the cell into their individual building blocks, which are then reassembled into new parts. The role of autophagy is crucial both in keeping cells healthy and in enabling them to fight different diseases. Physician scientists in UT Southwestern’s Center for Autophagy Research are deciphering how to manipulate the autophagy process in an effort to disrupt the progression of disease and promote health. In their latest findings reported online in the journal Nature, Center researchers were able to synthesize a peptide called Tat-beclin 1, which induces the autophagy process. Mice treated with Tat-beclin-1 were resistant to several infectious diseases, including West Nile virus and another mosquito-borne virus called chikungunya that is common to Asia, Africa, and India. In additional experiments, the team demonstrated that human cells treated with the peptide were resistant to HIV infection in a laboratory setting. “Because autophagy plays such a crucial role in regulating disease, autophagy-inducing agents such as the Tat?beclin 1 peptide may have potential for pharmaceutical development and the subsequent prevention and treatment of a broad range of human diseases,” said Dr. Beth Levine, Director of the Center for Autophagy Research and senior author of the study. Dr. Levine, Professor of Internal Medicine and Microbiology, is a Howard Hughes Medical Institute investigator at UT Southwestern. Disruption of the autophagy process is implicated in a wide variety of conditions including aging, and diseases, including cancers, neurodegenerative diseases such as Parkinson’s and Alzheimer’s, and infectious diseases such as those caused by West Nile and HIV viruses. UT Southwestern has applied for a patent on Tat-beclin-1. Peptides are strings of amino acids found in proteins. The Tat-beclin 1 peptide was derived from sequences in beclin 1, one of the first known proteins in mammals found to be essential for autophagy, a finding that was made by Dr. Levine’s laboratory. Her research has since demonstrated that defects in beclin 1 contribute to many types of disease. Conversely, beclin 1 activity and the autophagy pathway appear to be important for protection against breast, lung, and ovarian cancers, as well as for fighting off viral and bacterial infections, and for protecting individuals from neurodegenerative diseases and aging. ### The study was supported by grants from the National Institutes of Health, the National Science Foundation, the HHMI, the Netherlands Organization for Scientific Research-Earth and Life Sciences Open Program, Cancer Research United Kingdom, and a Robert A. Welch Foundation Award. Other UT Southwestern scientists involved include Dr. Sanae Shoji-Kawata, first author and former postdoctoral researcher now in Japan; Dr. Rhea Sumpter Jr., an instructor of internal medicine and member of the autophagy center; Dr. Matthew Leveno, assistant professor of internal medicine and autophagy center member; Dr. Carlos Huerta, former postdoctoral researcher of biochemistry now at Reata Pharmaceuticals; Dr. Nick Grishin, professor of biochemistry and HHMI investigator; Dr. Lisa Kinch, bioinformatics scientist; Zhongju Zou, research specialist; and Quhua Sun, computational biologist. Researchers from the University of California, San Diego; Rady Children’s Hospital-San Diego; Baylor College of Medicine in Houston; Washington University School of Medicine in St. Louis; Utrecht University, Utrecht, The Netherlands; Cancer Research UK, London; Massachusetts General Hospital, Harvard Medical School; the Broad Institute of Harvard and Massachusetts Institute of Technology; Columbia University College of Physicians and Surgeons; the HHMI; and University of California, Berkeley, also participated in the study. About UT Southwestern Medical Center UT Southwestern, one of the premier medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has many distinguished members, including five who have been awarded Nobel Prizes since 1985. Numbering more than 2,700, the faculty is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide medical care in 40 specialties to more than 100,000 hospitalized patients and oversee nearly 2 million outpatient visits a year. Contact: Russell Rian |
| UAB researchers cure type 1 diabetes in dogs Posted: 06 Feb 2013 09:00 PM PST Researchers from the Universitat Autònoma de Barcelona (UAB), led by Fàtima Bosch, have shown for the first time that it is possible to cure diabetes in large animals with a single session of gene therapy. As published this week in Diabetes, the principal journal for research on the disease, after a single gene therapy session, the dogs recover their health and no longer show symptoms of the disease. In some cases, monitoring continued for over four years, with no recurrence of symptoms.
The therapy is minimally invasive. It consists of a single session of various injections in the animal’s rear legs using simple needles that are commonly used in cosmetic treatments. These injections introduce gene therapy vectors, with a dual objective: to express the insulin gene, on the one hand, and that of glucokinase, on the other. Glucokinase is an enzyme that regulates the uptake of glucose from the blood. When both genes act simultaneously they function as a “glucose sensor”, which automatically regulates the uptake of glucose from the blood, thus reducing diabetic hyperglycemia (the excess of blood sugar associated with the disease). As Fàtima Bosch, the head researcher, points out, “this study is the first to demonstrate a long-term cure for diabetes in a large animal model using gene therapy.” This same research group had already tested this type of therapy on mice, but the excellent results obtained for the first time with large animals lays the foundations for the clinical translation of this gene therapy approach to veterinary medicine and eventually to diabetic patients. The study was led by the head of the UAB’s Centre for Animal Biotechnology and Gene Therapy (CBATEG) Fàtima Bosch, and involved the Department of Biochemistry and Molecular Biology of the UAB, the Department of Medicine and Animal Surgery of the UAB, the Faculty of Veterinary Science of the UAB, the Department of Animal Health and Anatomy of the UAB, the Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), the Children’s Hospital of Philadelphia (USA) and the Howard Hughes Medical Institute of Philadelphia (USA). A safe and efficacious gene therapy The study provides ample data showing the safety of gene therapy mediated by adeno-associated vectors (AAV) in diabetic dogs. The therapy has proved to be safe and efficacious: it is based on the transfer of two genes to the muscle of adult animals using a new generation of very safe vectors known as adeno-associated vectors. These vectors, derived from non-pathogenic viruses, are widely used in gene therapy and have been successful in treating several diseases. In fact, the first gene therapy medicine ever approved by the European Medicines Agency, named Glybera®, makes use of adeno-associated vectors to treat a metabolic disease caused by a deficiency of lipoprotein lipase and the resulting accumulation of triglycerides in the blood. Long-term control of the disease Dogs treated with a single administration of gene therapy showed good glucose control at all times, both when fasting and when fed, improving on that of dogs given daily insulin injections, and with no episodes of hypoglycemia, even after exercise. Furthermore, the dogs treated with adeno-associated vectors improved their body weight and had not developed secondary complications four years after the treatment. The study is the first to report optimal long-term control of diabetes in large animals. This had never before been achieved with any other innovative therapies for diabetes. The study is also the first to report that a single administration of genes to diabetic dogs is able to maintain normoglycemia over the long term (more than 4 years). As well as achieving normoglycemia, the dogs had normal levels of glycosylated proteins and developed no secondary complications of diabetes after more than 4 years with the disease. Application in diabetic patients There have been multiple clinical trials in which AAV vectors have been introduced into skeletal muscle, so the strategy reported in this study is feasible for clinical translation. Future safety and efficacy studies will provide the bases for initiating a clinical veterinary trial of diabetes treatment for companion animals, which will supply key information for eventual trials with humans. In conclusion, this study paves the way for the clinical translation of this approach to gene therapy to veterinary medicine, and eventually to diabetic patients. Diabetes mellitus Diabetes mellitus is the most common metabolic disease, and a large number of patients need insulin treatment to survive. In spite of the use of insulin injections to control the disease, these patients often develop serious secondary complications like blindness, kidney damage or amputation of limbs. Moreover, in order to achieve good blood glucose control, insulin has to be injected two or three times a day, which brings a risk of hypoglycemia episodes (lowering of blood sugar): an additional problem that comes on top of the other hardships of the treatment. Contact: Fàtima Bosch |
| Compound developed by scientists protects heart cells during and after attack Posted: 06 Feb 2013 09:00 PM PST Using two different compounds they developed, scientists from the Florida campus of The Scripps Research Institute (TSRI) have been able to show in animal models that inhibiting a specific enzyme protects heart cells and surrounding tissue against serious damage from heart attacks. The compounds also protect against additional injury from restored blood flow after an attack, a process known as reperfusion.
The study, which was led by Philip LoGrasso, a professor and senior scientific director of discovery biology at Scripps Florida, appears in the February 8, 2013 print edition of The Journal of Biological Chemistry. A heart attack severely restricts blood supply, starving heart cells and surrounding tissue of oxygen, which can cause enormous damage in relatively little time?sometimes in just a few minutes. Known as an ischemic cascade, this drop-off of oxygen results in a sudden crush of metabolic waste that damages cell membranes as well as the mitochondria, a part of the cell that generates chemical energy and is involved in cell growth and death. Unfortunately, restoring blood flow adds significantly to the damage, a serious medical issue when it comes to treating major ischemic events such as heart attack and stroke. Reperfusion re-invigorates production of free radicals and reactive oxygen species that attack and damage cells, exacerbating inflammation, turning loose white blood cells to attack otherwise salvageable cells and maybe even inducing potentially fatal cardiac arrhythmias. The new study found that inhibiting the enzyme, c-jun-N-terminal kinase (JNK), pronounced “junk,” protected against ischemic/reperfusion injury in rats, reducing the total volume of tissue death by as much as 34 percent. It also significantly reduced levels of reactive oxygen species and mitochondrial dysfunction. In earlier studies, TSRI scientists found that JNK migrates to the mitochondria upon oxidative stress. That migration, coupled with JNK activation, they found, is associated with a number of serious health issues, including liver damage, neuronal cell death, stroke and heart attack. The peptide and small molecule inhibitor (SR3306) developed by LoGrasso and his colleagues blocks those harmful effects, thereby reducing programmed cell death four-fold. “This is the same story,” said LoGrasso. “These just happen to be heart cells, but we know that oxidative stress kills cells, and JNK inhibition protects against this stress. Blocking the translocation of JNK to the mitochondria is essential for stopping this killing cascade and may be an effective treatment for damage done to heart cells during an ischemic/reperfusion event.” In addition, LoGrasso said, biomarkers that rise during a heart attack shrink in the presence of JNK inhibition, a clear indication that blocking JNK reduces the severity of the infarction. ### The first author of the study, “Inhibition of JNK Mitochondrial Localization and Signaling is Protective Against Ischemia-Reperfusion Injury in Rats,” is Jeremy W. Chambers of TSRI. Other authors include Alok Pachori, Shannon Howard and Sarah Iqbal, also of TSRI. This work was supported by the National Institutes of Health (grant number NS057153) and by the Saul and Theresa Esman Foundation. Contact: Eric Sauter |
| Scientists find key to growth of ‘bad’ bacteria in inflammatory bowel disease Posted: 06 Feb 2013 09:00 PM PST Scientists have long puzzled over why “bad” bacteria such as E. coli can thrive in the guts of those with inflammatory bowel disease (IBD), causing serious diarrhea. Now UC Davis researchers have discovered the answer?one that may be the first step toward finding new and better treatments for IBD.
The researchers discovered a biological mechanism by which harmful bacteria grow, edge out beneficial bacteria and damage the gut in IBD. This new understanding, published in the Feb. 8 issue of Science, may help researchers develop new treatments for IBD with fewer side effects than current therapies. IBD begins when “good” bacteria are mistakenly killed by the immune system, while harmful bacteria multiply resulting in inflammation and damage to the intestines, and chronic episodes of abdominal pain, cramping, diarrhea and other changes in bowel habits. It’s estimated that IBD, which includes ulcerative colitis and Crohn’s disease, affects 1.4 million people in the U.S., according to the Centers for Disease Control and Prevention. In test-tube and animal studies, the researchers found that potentially harmful bacteria in the intestine called Enterobacteriaceae use nitrate a byproduct formed during the intestinal inflammation in IBD to grow and thrive. Enterobacteriaceae strains include certain E. coli bacteria, which can worsen the intestinal damage of IBD. Eventually, the intestines of those with IBD become overrun by harmful bacteria, and the numbers of normal good bacteria in the gut decrease. “Much like humans use oxygen, E. coli can use nitrate as a replacement for oxygen to respire, produce energy and grow,” said lead author Andreas Baumler, a professor of medical microbiology and immunology at UC Davis. “In IBD, nitrate produced by inflammation in the gut allows E. coli to take a deep ‘breath,’ and beat out our beneficial microbes in the competition for nutrients,” he said. The inflammation in the intestines of those with IBD leads to the release of nitric oxide radicals that are powerful in attacking bacteria, Baumler explained. Yet these nitric oxide radicals are also very unstable, and eventually decompose into nitrate, which can be used by bacteria like E. coli to thrive and grow. By contrast, good bacteria in the gut grows through fermentation a much slower process. Determining the reasons why bacteria like E. coli can edge out good bacteria in the gut is crucial for determining new ways to halt the IBD disease process, according to Baumler. Current treatments for IBD suppress the immune response through antibiotics, corticosteroids or other powerful immune-modifying drugs. But long-term side effects can limit their use and their effectiveness for IBD patients. The UC Davis team’s research indicates that targeting the molecular pathways that generate nitric oxide and nitrate, as well as other molecules that feed harmful gut bacteria, could calm down and normalize the intestinal environment in IBD, Baumler noted. They are already doing research with one candidate drug that could halt the multiple pathways by which harmful bacteria thrive in IBD. “The idea would be to inhibit all pathways that produce molecules that can be used by bacteria such as E. coli for respiration and growth,” Baumler said. “Essentially you could then smother the bacteria.” ### Other study authors include Sebastian E. Winter, Maria G. Winter, Mariana N. Xavier, Parameth Thiennimitr, Victor Poon, A. Marijke Keestra, Ina Popova, Sanjai J. Parikh, Renee M. Tsolis, and Valley J. Stewart of UC Davis; and Richard C. Laughlin, Gabriel Gomez, Jing Wu, Sara D. Lawhon, and L. Garry Adams of Texas A&M University. This work was supported by the California Agricultural Experiment Station and Public Health Service grants AI089078, AI076246 and AI088122 along with a scholarship from the Faculty of Medicine, Chiang Mai University, Thailand. About UC Davis Health System
UC Davis Health System is improving lives and transforming health care by providing excellent patient care, conducting groundbreaking research, fostering inter-professional education, and creating innovative partnerships with the community. The academic health system includes one of the country’s best medical schools, a 619-bed acute-care teaching hospital, an 800-member physician’s practice group and the new Betty Irene Moore School of Nursing. It is home to a National Cancer Institute-designated comprehensive cancer center, an international neurodevelopmental institute, a stem cell institute and a comprehensive children’s hospital. Other nationally prominent centers focus on advancing telemedicine, improving vascular care, eliminating health disparities and translating research findings into new treatments for patients. Together, they make UC Davis a hub of innovation that is transforming health for all. Contact: Carole Gan |
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