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News Article | April 18, 2017
Site: www.eurekalert.org

Viruses that specifically kill bacteria, called bacteriophages, might one day help solve the growing problem of bacterial infections that are resistant to antibiotic treatment. Researchers at Baylor College of Medicine and the Michael E. DeBakey Veterans Affairs Medical Center have determined that phages can effectively reduce bacterial levels and improve the health of mice that are infected with deadly, antibiotic-resistant bacterial 'superbugs.' The study appears in Scientific Reports. "Our research team set out to determine whether phages can be effective at killing a large group of bacteria that have become resistant to antibiotics and cause deadly diseases in people," said corresponding author Dr. Anthony Maresso, associate professor of molecular virology and microbiology at Baylor. "We are running out of available options to treat patients who have these deadly bacterial infections; we need new ideas." When bacteria grow out of control, they can enter the blood stream and infect vital organs in the body. The body's immune system, an army of cells and molecules that fights back infections and other diseases, responds to the bacterial attack, defending the body from the infection. However, the immune response sometimes is excessive and can lead to tissue damage, organ failure and death, a process called sepsis. To end sepsis, bacterial growth has to stop. Antibiotic treatment usually can control bacterial growth and prevent the deadly consequences of sepsis, but increasing number of bacteria is becoming resistant to antibiotics. According to the National Institute of General Medical Sciences, sepsis affects more than 1 million people in the United States every year. About 50 percent of patients with sepsis die; this outnumbers the U.S. deaths caused by prostate cancer, breast cancer and AIDS combined. The number of sepsis cases per year is increasing, which underscores the need for new strategies to fight bacterial infections. In this study, the researchers investigated the possibility of recruiting phages in the fight against antibiotic-resistant bacteria, reviving the original idea of Felix d'Herelle, proposed in 1926. "The driving force behind this project was to find phages that would kill 12 strains of antibiotic-resistant bacteria that were isolated from patients," said co-author Dr. Robert Ramig, professor of molecular virology and microbiology at Baylor. "As the virologist on the team, my first contribution was to go phage hunting." "I have a number of phages in my lab, but none of them killed the antibiotic-resistant E. coli we were working on - the sequence type 131 currently pandemic across the globe," Ramig said. Birds and dogs often carry the bacteria the researchers were interested in, and may be one environmental reservoir of these pathogens. They also carry phages specific for those bacteria. Ramig, Maresso and Sabrina Green, a graduate student in the Molecular Virology Program at Baylor, went phage hunting in local parks and bird refuges to collect avian and canine feces. "We isolated a number of phages from animal feces," said Ramig. "No single phage would kill all the 12 bacterial strains, but collectively two or three of those phages would be able to kill all of those bacteria in cultures in the lab." This good news allowed the researchers to move on to the next step - determining whether the phages also would be able to kill the antibiotic-resistant bacteria in an animal model of sepsis. One of the animal models the researchers worked with mimics how cancer patients develop potentially life-threatening infections during their cancer treatment. "A number of cancer patients who undergo chemotherapy sometimes develop infections that come from bacteria that normally live in their own gut, usually without causing any symptoms," Green said. "Chemotherapy is intended to kill cancer cells, but one of the side effects is that it suppresses the immune system. A suppressed immune system is a major risk factor for infections with these bacteria, which sometimes also are multi-drug resistant." Working in Maresso's lab, Green developed a mouse model in which healthy mice received antibiotic-resistant bacteria that colonize their intestinal tract. "These mice showed no sign of disease," Maresso said. "But when the mice received chemotherapy," Green said, "the bacteria moved from their intestine to major organs - this led to a fatal sepsis-like infection." In this animal model in which the immune system cannot keep in check antibiotic-resistant bacteria, Green tested whether the phages were able to do so. "When the phages are delivered into the animals, their efficacy in reducing the levels of bacteria and improving health is dramatic," Maresso said. "But that is not what is truly remarkable," he continued. "What is remarkable is that these 'drugs' were discovered, isolated, identified and tested in a matter of weeks, and for less money than most of us probably spend in a month on groceries." Phages are very specific for certain species or strains of bacteria, but can be made broadly acting via cocktails, if desired. Thus, unlike antibiotics, using phages may not be associated with some of the side effects observed, such as clearing beneficial intestinal microbiota. They also don't infect human cells. Another advantage over antibiotics is that phages can evolve. Should resistance develop against one set of phages, new phages can be identified in the environment or evolved in the laboratory in a matter days. "On the other hand, an antibiotic is a chemical; it cannot change in real time," Maresso said. "It may take years to develop a new antibiotic and at costs that can run in the billions. But a phage can evolve to efficiently kill a resistant strain and then be propagated. It gives me great personal satisfaction when I think of the irony of this - the next anti-bacterial treatment may use the very same mechanisms bacteria have been using against us for 60-plus years now." Co-author Dr. Barbara Trautner, associate professor and director of clinical research in the Department of Surgery, associate professor of medicine at Baylor and also a researcher with Center for Innovations in Quality, Effectiveness and Safety at the Michael E. DeBakey Veterans Affairs Medical Center in Houston, and Ramig previously published a paper in which they showed that it is possible to take advantage of the phages' ability to change to fight bacterial infections. "In summary, we took four phages that specifically attacked bacteria of the group Pseudomonas, and they would kill four of 26 of these bacterial strains. Then, we evolved the phages in the lab, and in a month the new ones could kill 22 of the 26," Ramig said. "Envision the following possible future clinical scenario: a patient presents with antibiotic-resistant bacterial infection that is untreatable or only treatable with the most toxic of antibiotics. During the 48 hours it takes to identify the bacterial species and strain, physicians and scientists can go to a library of phages at hand, select those that are effective against this antibiotic-resistant bacterial strain and make a personalized cocktail of phages to treat the patient. Should resistance develop again, we will evolve another phage - right back at them!" Maresso said. "There are many ways to kill bacteria, but I know of no other way that has the potential to evolve in real time like phages do. And it's the best 'green' medicine - it's natural, safe thus far, relatively cheap and can be harnessed with the technical skills of a college biology major." Whereas the upside may be high, there is still some caution. "Phages are not infallible medicines," reflects Maresso. "The host's immune system sometimes can neutralize their activity and some phages just don't work well in animals. But we understand very little about any of these dynamics compared to those of other classes of drugs. At the very least, I think the evidence supports the notion that we should be giving phages some experimental attention." Co-author Jason T. Kaelber, predoctoral fellow of biochemistry at Baylor, also contributed to this project. This work was supported by a grant from the Mike Hogg Foundation and seed funds from Baylor College of Medicine. Cryoelectron microscopy was performed at the National Center for Macromolecular Imaging at Baylor and supported by grant P41 GM103832.


News Article | April 18, 2017
Site: phys.org

"Our research team set out to determine whether phages can be effective at killing a large group of bacteria that have become resistant to antibiotics and cause deadly diseases in people," said corresponding author Dr. Anthony Maresso, associate professor of molecular virology and microbiology at Baylor. "We are running out of available options to treat patients who have these deadly bacterial infections; we need new ideas." When bacteria grow out of control, they can enter the blood stream and infect vital organs in the body. The body's immune system, an army of cells and molecules that fights back infections and other diseases, responds to the bacterial attack, defending the body from the infection. However, the immune response sometimes is excessive and can lead to tissue damage, organ failure and death, a process called sepsis. To end sepsis, bacterial growth has to stop. Antibiotic treatment usually can control bacterial growth and prevent the deadly consequences of sepsis, but increasing number of bacteria is becoming resistant to antibiotics. According to the National Institute of General Medical Sciences, sepsis affects more than 1 million people in the United States every year. About 50 percent of patients with sepsis die; this outnumbers the U.S. deaths caused by prostate cancer, breast cancer and AIDS combined. The number of sepsis cases per year is increasing, which underscores the need for new strategies to fight bacterial infections. In this study, the researchers investigated the possibility of recruiting phages in the fight against antibiotic-resistant bacteria, reviving the original idea of Felix d'Herelle, proposed in 1926. "The driving force behind this project was to find phages that would kill 12 strains of antibiotic-resistant bacteria that were isolated from patients," said co-author Dr. Robert Ramig, professor of molecular virology and microbiology at Baylor. "As the virologist on the team, my first contribution was to go phage hunting." "I have a number of phages in my lab, but none of them killed the antibiotic-resistant E. coli we were working on - the sequence type 131 currently pandemic across the globe," Ramig said. Birds and dogs often carry the bacteria the researchers were interested in, and may be one environmental reservoir of these pathogens. They also carry phages specific for those bacteria. Ramig, Maresso and Sabrina Green, a graduate student in the Molecular Virology Program at Baylor, went phage hunting in local parks and bird refuges to collect avian and canine feces. "We isolated a number of phages from animal feces," said Ramig. "No single phage would kill all the 12 bacterial strains, but collectively two or three of those phages would be able to kill all of those bacteria in cultures in the lab." This good news allowed the researchers to move on to the next step - determining whether the phages also would be able to kill the antibiotic-resistant bacteria in an animal model of sepsis. One of the animal models the researchers worked with mimics how cancer patients develop potentially life-threatening infections during their cancer treatment. "A number of cancer patients who undergo chemotherapy sometimes develop infections that come from bacteria that normally live in their own gut, usually without causing any symptoms," Green said. "Chemotherapy is intended to kill cancer cells, but one of the side effects is that it suppresses the immune system. A suppressed immune system is a major risk factor for infections with these bacteria, which sometimes also are multi-drug resistant." Working in Maresso's lab, Green developed a mouse model in which healthy mice received antibiotic-resistant bacteria that colonize their intestinal tract. "These mice showed no sign of disease," Maresso said. "But when the mice received chemotherapy," Green said, "the bacteria moved from their intestine to major organs - this led to a fatal sepsis-like infection." In this animal model in which the immune system cannot keep in check antibiotic-resistant bacteria, Green tested whether the phages were able to do so. "When the phages are delivered into the animals, their efficacy in reducing the levels of bacteria and improving health is dramatic," Maresso said. "But that is not what is truly remarkable," he continued. "What is remarkable is that these 'drugs' were discovered, isolated, identified and tested in a matter of weeks, and for less money than most of us probably spend in a month on groceries." Phages are very specific for certain species or strains of bacteria, but can be made broadly acting via cocktails, if desired. Thus, unlike antibiotics, using phages may not be associated with some of the side effects observed, such as clearing beneficial intestinal microbiota. They also don't infect human cells. Another advantage over antibiotics is that phages can evolve. Should resistance develop against one set of phages, new phages can be identified in the environment or evolved in the laboratory in a matter days. "On the other hand, an antibiotic is a chemical; it cannot change in real time," Maresso said. "It may take years to develop a new antibiotic and at costs that can run in the billions. But a phage can evolve to efficiently kill a resistant strain and then be propagated. It gives me great personal satisfaction when I think of the irony of this - the next anti-bacterial treatment may use the very same mechanisms bacteria have been using against us for 60-plus years now." Co-author Dr. Barbara Trautner, associate professor and director of clinical research in the Department of Surgery, associate professor of medicine at Baylor and also a researcher with Center for Innovations in Quality, Effectiveness and Safety at the Michael E. DeBakey Veterans Affairs Medical Center in Houston, and Ramig previously published a paper in which they showed that it is possible to take advantage of the phages' ability to change to fight bacterial infections. "In summary, we took four phages that specifically attacked bacteria of the group Pseudomonas, and they would kill four of 26 of these bacterial strains. Then, we evolved the phages in the lab, and in a month the new ones could kill 22 of the 26," Ramig said. "Envision the following possible future clinical scenario: a patient presents with antibiotic-resistant bacterial infection that is untreatable or only treatable with the most toxic of antibiotics. During the 48 hours it takes to identify the bacterial species and strain, physicians and scientists can go to a library of phages at hand, select those that are effective against this antibiotic-resistant bacterial strain and make a personalized cocktail of phages to treat the patient. Should resistance develop again, we will evolve another phage - right back at them!" Maresso said. "There are many ways to kill bacteria, but I know of no other way that has the potential to evolve in real time like phages do. And it's the best 'green' medicine - it's natural, safe thus far, relatively cheap and can be harnessed with the technical skills of a college biology major." Whereas the upside may be high, there is still some caution. "Phages are not infallible medicines," reflects Maresso. "The host's immune system sometimes can neutralize their activity and some phages just don't work well in animals. But we understand very little about any of these dynamics compared to those of other classes of drugs. At the very least, I think the evidence supports the notion that we should be giving phages some experimental attention." More information: Sabrina I. Green et al, Bacteriophages from ExPEC Reservoirs Kill Pandemic Multidrug-Resistant Strains of Clonal Group ST131 in Animal Models of Bacteremia, Scientific Reports (2017). DOI: 10.1038/srep46151


TEL-AVIV, Israel, May 04, 2017 (GLOBE NEWSWIRE) -- RedHill Biopharma Ltd. (NASDAQ:RDHL) (TASE:RDHL) (“RedHill” or the “Company”), a specialty biopharmaceutical company primarily focused on the development and commercialization of late clinical-stage, proprietary, orally-administered, small molecule drugs for gastrointestinal and inflammatory diseases and cancer, today announced the presentation of a poster at Digestive Disease Week (DDW) 2017. The poster (presentation number: Sa1200) will be presented by Ira Kalfus, MD, Medical Director at RedHill, on Saturday, May 6, 2017 from 12:00 PM to 2:00 PM CDT, in Chicago, IL. The poster1 presentation, entitled “ERADICATE Hp: A Randomized, Double-Blind, Placebo-Controlled Phase III Study to Assess the Safety and Efficacy of Rifabutin Triple Therapy (RHB-105) for Helicobacter pylori (H. pylori) Infection in Dyspepsia Patients” describes the previously reported positive final results of the ERADICATE Hp first Phase III study with RHB-105 for H. pylori infection. RHB-105 is a proprietary, fixed-dose, oral combination therapy for the eradication of H. pylori infection. The ERADICATE Hp first Phase III study with RHB-105 successfully met its protocol-defined mITT primary endpoint of superiority over historical standard-of-care (SoC) eradication rate of 70%, with high statistical significance (p<0.001). The study results demonstrated 89.4% efficacy in eradicating H. pylori infection with RHB-105. Notably, the 89.4% efficacy in eradicating H. pylori infection with RHB-105 was also superior to subsequent open-label treatment with SoC therapies of patients in the placebo arm of the ERADICATE Hp study, which demonstrated 63% eradication rate in the mITT population (p=0.006), further supporting the potential efficacy of RHB-105 as a treatment for H. pylori infection. Treatment with RHB-105 appeared to be safe and well tolerated. A confirmatory Phase III study is planned to be initiated in the second quarter of 2017. The two-arm, randomized, double-blind, active comparator confirmatory Phase III study will compare RHB-105 against a dual therapy amoxicillin and omeprazole regimen at equivalent doses. The study is planned to enroll approximately 440 patients in up to 55 clinical sites in the U.S. Subject to its successful completion, the planned confirmatory Phase III study, along with the results from the successfully completed first Phase III ERADICATE Hp study with RHB-105 and data to be obtained from an ongoing supportive PK program, are expected to support a U.S. New Drug Application (NDA) for RHB-105. About RHB-105: RHB-105 is a new and proprietary fixed-dose oral combination therapy of two antibiotics and a proton pump inhibitor (PPI) in an all-in-one oral capsule with a planned indication for the treatment of H. pylori infection. H. pylori bacterial infection is a major cause of chronic gastritis, peptic ulcer disease, gastric cancer and mucosa-associated lymphoid tissue (MALT) lymphoma. A first Phase III study with RHB-105 was completed in the U.S. with positive results (ERADICATE Hp study). The study demonstrated an overall success rate of 89.4% in eradicating H. pylori, and met its protocol-defined primary endpoint of superiority in eradication of H. pylori infection over historical standard-of-care efficacy levels of 70%, with high statistical significance (p<0.001). A confirmatory Phase III study is planned to be initiated in the U.S in the second quarter of 2017. Additional studies may be required, subject to FDA review. RHB-105 has been granted Qualifying Infectious Disease Product (QIDP) designation by the FDA, providing a Fast-Track development pathway, as well as NDA Priority Review status, potentially leading to a shorter NDA review time by the FDA, if filed. If approved, RHB-105 will also receive an additional five years of exclusivity, in addition to the standard exclusivity period, for a total of 8 years of U.S. market exclusivity. About RedHill Biopharma Ltd.: RedHill Biopharma Ltd. (NASDAQ:RDHL) (Tel-Aviv Stock Exchange:RDHL) is a specialty biopharmaceutical company headquartered in Israel, primarily focused on the development and commercialization of late clinical-stage, proprietary, orally-administered, small molecule drugs for the treatment of gastrointestinal and inflammatory diseases and cancer. RedHill has a U.S. co-promotion agreement with Concordia for Donnatal®, a prescription oral adjunctive drug used in the treatment of IBS and acute enterocolitis, as well as an exclusive license agreement with Entera Health for EnteraGam®, a medical food intended for the dietary management, under medical supervision, of chronic diarrhea and loose stools. RedHill’s clinical-stage pipeline includes: (i) RHB-105 - an oral combination therapy for the treatment of Helicobacter pylori infection with successful results from a first Phase III study; (ii) RHB-104 - an oral combination therapy for the treatment of Crohn's disease with an ongoing first Phase III study, a completed proof-of-concept Phase IIa study for multiple sclerosis and QIDP status for nontuberculous mycobacteria (NTM) infections; (iii) BEKINDA® (RHB-102) - a once-daily oral pill formulation of ondansetron with an ongoing Phase III study for acute gastroenteritis and gastritis and an ongoing Phase II study for IBS-D; (iv) RHB-106 - an encapsulated bowel preparation licensed to Salix Pharmaceuticals, Ltd.; (v) YELIVA® (ABC294640) - a Phase II-stage, orally-administered, first-in-class SK2 selective inhibitor targeting multiple oncology, inflammatory and gastrointestinal indications; (vi) MESUPRON - a Phase II-stage first-in-class, orally-administered protease inhibitor, targeting pancreatic cancer and other solid tumors and (vii) RIZAPORT® (RHB-103) - an oral thin film formulation of rizatriptan for acute migraines, with a U.S. NDA currently under discussion with the FDA and marketing authorization received in two EU member states under the European Decentralized Procedure (DCP). More information about the Company is available at: www.redhillbio.com. 1 The poster was authored by Ira N. Kalfus, MD, Medical Director, RedHill Biopharma; Gilead Raday, Chief Operating Officer, RedHill Biopharma; Reza Fathi, PhD, Senior VP R&D, RedHill Biopharma and David Y. Graham, MD, Professor of Medicine, Molecular Virology and Microbiology, Baylor College of Medicine. This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Such statements may be preceded by the words “intends,” “may,” “will,” “plans,” “expects,” “anticipates,” “projects,” “predicts,” “estimates,” “aims,” “believes,” “hopes,” “potential” or similar words. Forward-looking statements are based on certain assumptions and are subject to various known and unknown risks and uncertainties, many of which are beyond the Company’s control, and cannot be predicted or quantified and consequently, actual results may differ materially from those expressed or implied by such forward-looking statements. Such risks and uncertainties include, without limitation, risks and uncertainties associated with (i) the initiation, timing, progress and results of the Company’s research, manufacturing, preclinical studies, clinical trials, and other therapeutic candidate development efforts; (ii) the Company’s ability to advance its therapeutic candidates into clinical trials or to successfully complete its preclinical studies or clinical trials; (iii) the extent and number of additional studies that the Company may be required to conduct and the Company’s receipt of regulatory approvals for its therapeutic candidates, and the timing of other regulatory filings, approvals and feedback; (iv) the manufacturing, clinical development, commercialization, and market acceptance of the Company’s therapeutic candidates; (v) the Company’s ability to successfully market Donnatal® and EnteraGam®, (vi) the Company’s ability to establish and maintain corporate collaborations; (vii) the Company's ability to acquire products approved for marketing in the U.S. that achieve commercial success and build its own marketing and commercialization capabilities; (viii) the interpretation of the properties and characteristics of the Company’s therapeutic candidates and of the results obtained with its therapeutic candidates in research, preclinical studies or clinical trials; (ix) the implementation of the Company’s business model, strategic plans for its business and therapeutic candidates; (x) the scope of protection the Company is able to establish and maintain for intellectual property rights covering its therapeutic candidates and its ability to operate its business without infringing the intellectual property rights of others; (xi) parties from whom the Company licenses its intellectual property defaulting in their obligations to the Company; and (xii) estimates of the Company’s expenses, future revenues capital requirements and the Company’s needs for additional financing; (xiii) competitive companies and technologies within the Company’s industry. More detailed information about the Company and the risk factors that may affect the realization of forward-looking statements is set forth in the Company's filings with the Securities and Exchange Commission (SEC), including the Company's Annual Report on Form 20-F filed with the SEC on February 23, 2017. All forward-looking statements included in this Press Release are made only as of the date of this Press Release. We assume no obligation to update any written or oral forward-looking statement unless required by law.


TEL-AVIV, Israel, May 04, 2017 (GLOBE NEWSWIRE) -- RedHill Biopharma Ltd. (NASDAQ:RDHL) (TASE:RDHL) (“RedHill” or the “Company”), a specialty biopharmaceutical company primarily focused on the development and commercialization of late clinical-stage, proprietary, orally-administered, small molecule drugs for gastrointestinal and inflammatory diseases and cancer, today announced the presentation of a poster at Digestive Disease Week (DDW) 2017. The poster (presentation number: Sa1200) will be presented by Ira Kalfus, MD, Medical Director at RedHill, on Saturday, May 6, 2017 from 12:00 PM to 2:00 PM CDT, in Chicago, IL. The poster1 presentation, entitled “ERADICATE Hp: A Randomized, Double-Blind, Placebo-Controlled Phase III Study to Assess the Safety and Efficacy of Rifabutin Triple Therapy (RHB-105) for Helicobacter pylori (H. pylori) Infection in Dyspepsia Patients” describes the previously reported positive final results of the ERADICATE Hp first Phase III study with RHB-105 for H. pylori infection. RHB-105 is a proprietary, fixed-dose, oral combination therapy for the eradication of H. pylori infection. The ERADICATE Hp first Phase III study with RHB-105 successfully met its protocol-defined mITT primary endpoint of superiority over historical standard-of-care (SoC) eradication rate of 70%, with high statistical significance (p<0.001). The study results demonstrated 89.4% efficacy in eradicating H. pylori infection with RHB-105. Notably, the 89.4% efficacy in eradicating H. pylori infection with RHB-105 was also superior to subsequent open-label treatment with SoC therapies of patients in the placebo arm of the ERADICATE Hp study, which demonstrated 63% eradication rate in the mITT population (p=0.006), further supporting the potential efficacy of RHB-105 as a treatment for H. pylori infection. Treatment with RHB-105 appeared to be safe and well tolerated. A confirmatory Phase III study is planned to be initiated in the second quarter of 2017. The two-arm, randomized, double-blind, active comparator confirmatory Phase III study will compare RHB-105 against a dual therapy amoxicillin and omeprazole regimen at equivalent doses. The study is planned to enroll approximately 440 patients in up to 55 clinical sites in the U.S. Subject to its successful completion, the planned confirmatory Phase III study, along with the results from the successfully completed first Phase III ERADICATE Hp study with RHB-105 and data to be obtained from an ongoing supportive PK program, are expected to support a U.S. New Drug Application (NDA) for RHB-105. About RHB-105: RHB-105 is a new and proprietary fixed-dose oral combination therapy of two antibiotics and a proton pump inhibitor (PPI) in an all-in-one oral capsule with a planned indication for the treatment of H. pylori infection. H. pylori bacterial infection is a major cause of chronic gastritis, peptic ulcer disease, gastric cancer and mucosa-associated lymphoid tissue (MALT) lymphoma. A first Phase III study with RHB-105 was completed in the U.S. with positive results (ERADICATE Hp study). The study demonstrated an overall success rate of 89.4% in eradicating H. pylori, and met its protocol-defined primary endpoint of superiority in eradication of H. pylori infection over historical standard-of-care efficacy levels of 70%, with high statistical significance (p<0.001). A confirmatory Phase III study is planned to be initiated in the U.S in the second quarter of 2017. Additional studies may be required, subject to FDA review. RHB-105 has been granted Qualifying Infectious Disease Product (QIDP) designation by the FDA, providing a Fast-Track development pathway, as well as NDA Priority Review status, potentially leading to a shorter NDA review time by the FDA, if filed. If approved, RHB-105 will also receive an additional five years of exclusivity, in addition to the standard exclusivity period, for a total of 8 years of U.S. market exclusivity. About RedHill Biopharma Ltd.: RedHill Biopharma Ltd. (NASDAQ:RDHL) (Tel-Aviv Stock Exchange:RDHL) is a specialty biopharmaceutical company headquartered in Israel, primarily focused on the development and commercialization of late clinical-stage, proprietary, orally-administered, small molecule drugs for the treatment of gastrointestinal and inflammatory diseases and cancer. RedHill has a U.S. co-promotion agreement with Concordia for Donnatal®, a prescription oral adjunctive drug used in the treatment of IBS and acute enterocolitis, as well as an exclusive license agreement with Entera Health for EnteraGam®, a medical food intended for the dietary management, under medical supervision, of chronic diarrhea and loose stools. RedHill’s clinical-stage pipeline includes: (i) RHB-105 - an oral combination therapy for the treatment of Helicobacter pylori infection with successful results from a first Phase III study; (ii) RHB-104 - an oral combination therapy for the treatment of Crohn's disease with an ongoing first Phase III study, a completed proof-of-concept Phase IIa study for multiple sclerosis and QIDP status for nontuberculous mycobacteria (NTM) infections; (iii) BEKINDA® (RHB-102) - a once-daily oral pill formulation of ondansetron with an ongoing Phase III study for acute gastroenteritis and gastritis and an ongoing Phase II study for IBS-D; (iv) RHB-106 - an encapsulated bowel preparation licensed to Salix Pharmaceuticals, Ltd.; (v) YELIVA® (ABC294640) - a Phase II-stage, orally-administered, first-in-class SK2 selective inhibitor targeting multiple oncology, inflammatory and gastrointestinal indications; (vi) MESUPRON - a Phase II-stage first-in-class, orally-administered protease inhibitor, targeting pancreatic cancer and other solid tumors and (vii) RIZAPORT® (RHB-103) - an oral thin film formulation of rizatriptan for acute migraines, with a U.S. NDA currently under discussion with the FDA and marketing authorization received in two EU member states under the European Decentralized Procedure (DCP). More information about the Company is available at: www.redhillbio.com. 1 The poster was authored by Ira N. Kalfus, MD, Medical Director, RedHill Biopharma; Gilead Raday, Chief Operating Officer, RedHill Biopharma; Reza Fathi, PhD, Senior VP R&D, RedHill Biopharma and David Y. Graham, MD, Professor of Medicine, Molecular Virology and Microbiology, Baylor College of Medicine. This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Such statements may be preceded by the words “intends,” “may,” “will,” “plans,” “expects,” “anticipates,” “projects,” “predicts,” “estimates,” “aims,” “believes,” “hopes,” “potential” or similar words. Forward-looking statements are based on certain assumptions and are subject to various known and unknown risks and uncertainties, many of which are beyond the Company’s control, and cannot be predicted or quantified and consequently, actual results may differ materially from those expressed or implied by such forward-looking statements. Such risks and uncertainties include, without limitation, risks and uncertainties associated with (i) the initiation, timing, progress and results of the Company’s research, manufacturing, preclinical studies, clinical trials, and other therapeutic candidate development efforts; (ii) the Company’s ability to advance its therapeutic candidates into clinical trials or to successfully complete its preclinical studies or clinical trials; (iii) the extent and number of additional studies that the Company may be required to conduct and the Company’s receipt of regulatory approvals for its therapeutic candidates, and the timing of other regulatory filings, approvals and feedback; (iv) the manufacturing, clinical development, commercialization, and market acceptance of the Company’s therapeutic candidates; (v) the Company’s ability to successfully market Donnatal® and EnteraGam®, (vi) the Company’s ability to establish and maintain corporate collaborations; (vii) the Company's ability to acquire products approved for marketing in the U.S. that achieve commercial success and build its own marketing and commercialization capabilities; (viii) the interpretation of the properties and characteristics of the Company’s therapeutic candidates and of the results obtained with its therapeutic candidates in research, preclinical studies or clinical trials; (ix) the implementation of the Company’s business model, strategic plans for its business and therapeutic candidates; (x) the scope of protection the Company is able to establish and maintain for intellectual property rights covering its therapeutic candidates and its ability to operate its business without infringing the intellectual property rights of others; (xi) parties from whom the Company licenses its intellectual property defaulting in their obligations to the Company; and (xii) estimates of the Company’s expenses, future revenues capital requirements and the Company’s needs for additional financing; (xiii) competitive companies and technologies within the Company’s industry. More detailed information about the Company and the risk factors that may affect the realization of forward-looking statements is set forth in the Company's filings with the Securities and Exchange Commission (SEC), including the Company's Annual Report on Form 20-F filed with the SEC on February 23, 2017. All forward-looking statements included in this Press Release are made only as of the date of this Press Release. We assume no obligation to update any written or oral forward-looking statement unless required by law.


TEL-AVIV, Israel, May 04, 2017 (GLOBE NEWSWIRE) -- RedHill Biopharma Ltd. (NASDAQ:RDHL) (TASE:RDHL) (“RedHill” or the “Company”), a specialty biopharmaceutical company primarily focused on the development and commercialization of late clinical-stage, proprietary, orally-administered, small molecule drugs for gastrointestinal and inflammatory diseases and cancer, today announced the presentation of a poster at Digestive Disease Week (DDW) 2017. The poster (presentation number: Sa1200) will be presented by Ira Kalfus, MD, Medical Director at RedHill, on Saturday, May 6, 2017 from 12:00 PM to 2:00 PM CDT, in Chicago, IL. The poster1 presentation, entitled “ERADICATE Hp: A Randomized, Double-Blind, Placebo-Controlled Phase III Study to Assess the Safety and Efficacy of Rifabutin Triple Therapy (RHB-105) for Helicobacter pylori (H. pylori) Infection in Dyspepsia Patients” describes the previously reported positive final results of the ERADICATE Hp first Phase III study with RHB-105 for H. pylori infection. RHB-105 is a proprietary, fixed-dose, oral combination therapy for the eradication of H. pylori infection. The ERADICATE Hp first Phase III study with RHB-105 successfully met its protocol-defined mITT primary endpoint of superiority over historical standard-of-care (SoC) eradication rate of 70%, with high statistical significance (p<0.001). The study results demonstrated 89.4% efficacy in eradicating H. pylori infection with RHB-105. Notably, the 89.4% efficacy in eradicating H. pylori infection with RHB-105 was also superior to subsequent open-label treatment with SoC therapies of patients in the placebo arm of the ERADICATE Hp study, which demonstrated 63% eradication rate in the mITT population (p=0.006), further supporting the potential efficacy of RHB-105 as a treatment for H. pylori infection. Treatment with RHB-105 appeared to be safe and well tolerated. A confirmatory Phase III study is planned to be initiated in the second quarter of 2017. The two-arm, randomized, double-blind, active comparator confirmatory Phase III study will compare RHB-105 against a dual therapy amoxicillin and omeprazole regimen at equivalent doses. The study is planned to enroll approximately 440 patients in up to 55 clinical sites in the U.S. Subject to its successful completion, the planned confirmatory Phase III study, along with the results from the successfully completed first Phase III ERADICATE Hp study with RHB-105 and data to be obtained from an ongoing supportive PK program, are expected to support a U.S. New Drug Application (NDA) for RHB-105. About RHB-105: RHB-105 is a new and proprietary fixed-dose oral combination therapy of two antibiotics and a proton pump inhibitor (PPI) in an all-in-one oral capsule with a planned indication for the treatment of H. pylori infection. H. pylori bacterial infection is a major cause of chronic gastritis, peptic ulcer disease, gastric cancer and mucosa-associated lymphoid tissue (MALT) lymphoma. A first Phase III study with RHB-105 was completed in the U.S. with positive results (ERADICATE Hp study). The study demonstrated an overall success rate of 89.4% in eradicating H. pylori, and met its protocol-defined primary endpoint of superiority in eradication of H. pylori infection over historical standard-of-care efficacy levels of 70%, with high statistical significance (p<0.001). A confirmatory Phase III study is planned to be initiated in the U.S in the second quarter of 2017. Additional studies may be required, subject to FDA review. RHB-105 has been granted Qualifying Infectious Disease Product (QIDP) designation by the FDA, providing a Fast-Track development pathway, as well as NDA Priority Review status, potentially leading to a shorter NDA review time by the FDA, if filed. If approved, RHB-105 will also receive an additional five years of exclusivity, in addition to the standard exclusivity period, for a total of 8 years of U.S. market exclusivity. About RedHill Biopharma Ltd.: RedHill Biopharma Ltd. (NASDAQ:RDHL) (Tel-Aviv Stock Exchange:RDHL) is a specialty biopharmaceutical company headquartered in Israel, primarily focused on the development and commercialization of late clinical-stage, proprietary, orally-administered, small molecule drugs for the treatment of gastrointestinal and inflammatory diseases and cancer. RedHill has a U.S. co-promotion agreement with Concordia for Donnatal®, a prescription oral adjunctive drug used in the treatment of IBS and acute enterocolitis, as well as an exclusive license agreement with Entera Health for EnteraGam®, a medical food intended for the dietary management, under medical supervision, of chronic diarrhea and loose stools. RedHill’s clinical-stage pipeline includes: (i) RHB-105 - an oral combination therapy for the treatment of Helicobacter pylori infection with successful results from a first Phase III study; (ii) RHB-104 - an oral combination therapy for the treatment of Crohn's disease with an ongoing first Phase III study, a completed proof-of-concept Phase IIa study for multiple sclerosis and QIDP status for nontuberculous mycobacteria (NTM) infections; (iii) BEKINDA® (RHB-102) - a once-daily oral pill formulation of ondansetron with an ongoing Phase III study for acute gastroenteritis and gastritis and an ongoing Phase II study for IBS-D; (iv) RHB-106 - an encapsulated bowel preparation licensed to Salix Pharmaceuticals, Ltd.; (v) YELIVA® (ABC294640) - a Phase II-stage, orally-administered, first-in-class SK2 selective inhibitor targeting multiple oncology, inflammatory and gastrointestinal indications; (vi) MESUPRON - a Phase II-stage first-in-class, orally-administered protease inhibitor, targeting pancreatic cancer and other solid tumors and (vii) RIZAPORT® (RHB-103) - an oral thin film formulation of rizatriptan for acute migraines, with a U.S. NDA currently under discussion with the FDA and marketing authorization received in two EU member states under the European Decentralized Procedure (DCP). More information about the Company is available at: www.redhillbio.com. 1 The poster was authored by Ira N. Kalfus, MD, Medical Director, RedHill Biopharma; Gilead Raday, Chief Operating Officer, RedHill Biopharma; Reza Fathi, PhD, Senior VP R&D, RedHill Biopharma and David Y. Graham, MD, Professor of Medicine, Molecular Virology and Microbiology, Baylor College of Medicine. This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Such statements may be preceded by the words “intends,” “may,” “will,” “plans,” “expects,” “anticipates,” “projects,” “predicts,” “estimates,” “aims,” “believes,” “hopes,” “potential” or similar words. Forward-looking statements are based on certain assumptions and are subject to various known and unknown risks and uncertainties, many of which are beyond the Company’s control, and cannot be predicted or quantified and consequently, actual results may differ materially from those expressed or implied by such forward-looking statements. Such risks and uncertainties include, without limitation, risks and uncertainties associated with (i) the initiation, timing, progress and results of the Company’s research, manufacturing, preclinical studies, clinical trials, and other therapeutic candidate development efforts; (ii) the Company’s ability to advance its therapeutic candidates into clinical trials or to successfully complete its preclinical studies or clinical trials; (iii) the extent and number of additional studies that the Company may be required to conduct and the Company’s receipt of regulatory approvals for its therapeutic candidates, and the timing of other regulatory filings, approvals and feedback; (iv) the manufacturing, clinical development, commercialization, and market acceptance of the Company’s therapeutic candidates; (v) the Company’s ability to successfully market Donnatal® and EnteraGam®, (vi) the Company’s ability to establish and maintain corporate collaborations; (vii) the Company's ability to acquire products approved for marketing in the U.S. that achieve commercial success and build its own marketing and commercialization capabilities; (viii) the interpretation of the properties and characteristics of the Company’s therapeutic candidates and of the results obtained with its therapeutic candidates in research, preclinical studies or clinical trials; (ix) the implementation of the Company’s business model, strategic plans for its business and therapeutic candidates; (x) the scope of protection the Company is able to establish and maintain for intellectual property rights covering its therapeutic candidates and its ability to operate its business without infringing the intellectual property rights of others; (xi) parties from whom the Company licenses its intellectual property defaulting in their obligations to the Company; and (xii) estimates of the Company’s expenses, future revenues capital requirements and the Company’s needs for additional financing; (xiii) competitive companies and technologies within the Company’s industry. More detailed information about the Company and the risk factors that may affect the realization of forward-looking statements is set forth in the Company's filings with the Securities and Exchange Commission (SEC), including the Company's Annual Report on Form 20-F filed with the SEC on February 23, 2017. All forward-looking statements included in this Press Release are made only as of the date of this Press Release. We assume no obligation to update any written or oral forward-looking statement unless required by law.


TEL-AVIV, Israel, May 04, 2017 (GLOBE NEWSWIRE) -- RedHill Biopharma Ltd. (NASDAQ:RDHL) (TASE:RDHL) (“RedHill” or the “Company”), a specialty biopharmaceutical company primarily focused on the development and commercialization of late clinical-stage, proprietary, orally-administered, small molecule drugs for gastrointestinal and inflammatory diseases and cancer, today announced the presentation of a poster at Digestive Disease Week (DDW) 2017. The poster (presentation number: Sa1200) will be presented by Ira Kalfus, MD, Medical Director at RedHill, on Saturday, May 6, 2017 from 12:00 PM to 2:00 PM CDT, in Chicago, IL. The poster1 presentation, entitled “ERADICATE Hp: A Randomized, Double-Blind, Placebo-Controlled Phase III Study to Assess the Safety and Efficacy of Rifabutin Triple Therapy (RHB-105) for Helicobacter pylori (H. pylori) Infection in Dyspepsia Patients” describes the previously reported positive final results of the ERADICATE Hp first Phase III study with RHB-105 for H. pylori infection. RHB-105 is a proprietary, fixed-dose, oral combination therapy for the eradication of H. pylori infection. The ERADICATE Hp first Phase III study with RHB-105 successfully met its protocol-defined mITT primary endpoint of superiority over historical standard-of-care (SoC) eradication rate of 70%, with high statistical significance (p<0.001). The study results demonstrated 89.4% efficacy in eradicating H. pylori infection with RHB-105. Notably, the 89.4% efficacy in eradicating H. pylori infection with RHB-105 was also superior to subsequent open-label treatment with SoC therapies of patients in the placebo arm of the ERADICATE Hp study, which demonstrated 63% eradication rate in the mITT population (p=0.006), further supporting the potential efficacy of RHB-105 as a treatment for H. pylori infection. Treatment with RHB-105 appeared to be safe and well tolerated. A confirmatory Phase III study is planned to be initiated in the second quarter of 2017. The two-arm, randomized, double-blind, active comparator confirmatory Phase III study will compare RHB-105 against a dual therapy amoxicillin and omeprazole regimen at equivalent doses. The study is planned to enroll approximately 440 patients in up to 55 clinical sites in the U.S. Subject to its successful completion, the planned confirmatory Phase III study, along with the results from the successfully completed first Phase III ERADICATE Hp study with RHB-105 and data to be obtained from an ongoing supportive PK program, are expected to support a U.S. New Drug Application (NDA) for RHB-105. About RHB-105: RHB-105 is a new and proprietary fixed-dose oral combination therapy of two antibiotics and a proton pump inhibitor (PPI) in an all-in-one oral capsule with a planned indication for the treatment of H. pylori infection. H. pylori bacterial infection is a major cause of chronic gastritis, peptic ulcer disease, gastric cancer and mucosa-associated lymphoid tissue (MALT) lymphoma. A first Phase III study with RHB-105 was completed in the U.S. with positive results (ERADICATE Hp study). The study demonstrated an overall success rate of 89.4% in eradicating H. pylori, and met its protocol-defined primary endpoint of superiority in eradication of H. pylori infection over historical standard-of-care efficacy levels of 70%, with high statistical significance (p<0.001). A confirmatory Phase III study is planned to be initiated in the U.S in the second quarter of 2017. Additional studies may be required, subject to FDA review. RHB-105 has been granted Qualifying Infectious Disease Product (QIDP) designation by the FDA, providing a Fast-Track development pathway, as well as NDA Priority Review status, potentially leading to a shorter NDA review time by the FDA, if filed. If approved, RHB-105 will also receive an additional five years of exclusivity, in addition to the standard exclusivity period, for a total of 8 years of U.S. market exclusivity. About RedHill Biopharma Ltd.: RedHill Biopharma Ltd. (NASDAQ:RDHL) (Tel-Aviv Stock Exchange:RDHL) is a specialty biopharmaceutical company headquartered in Israel, primarily focused on the development and commercialization of late clinical-stage, proprietary, orally-administered, small molecule drugs for the treatment of gastrointestinal and inflammatory diseases and cancer. RedHill has a U.S. co-promotion agreement with Concordia for Donnatal®, a prescription oral adjunctive drug used in the treatment of IBS and acute enterocolitis, as well as an exclusive license agreement with Entera Health for EnteraGam®, a medical food intended for the dietary management, under medical supervision, of chronic diarrhea and loose stools. RedHill’s clinical-stage pipeline includes: (i) RHB-105 - an oral combination therapy for the treatment of Helicobacter pylori infection with successful results from a first Phase III study; (ii) RHB-104 - an oral combination therapy for the treatment of Crohn's disease with an ongoing first Phase III study, a completed proof-of-concept Phase IIa study for multiple sclerosis and QIDP status for nontuberculous mycobacteria (NTM) infections; (iii) BEKINDA® (RHB-102) - a once-daily oral pill formulation of ondansetron with an ongoing Phase III study for acute gastroenteritis and gastritis and an ongoing Phase II study for IBS-D; (iv) RHB-106 - an encapsulated bowel preparation licensed to Salix Pharmaceuticals, Ltd.; (v) YELIVA® (ABC294640) - a Phase II-stage, orally-administered, first-in-class SK2 selective inhibitor targeting multiple oncology, inflammatory and gastrointestinal indications; (vi) MESUPRON - a Phase II-stage first-in-class, orally-administered protease inhibitor, targeting pancreatic cancer and other solid tumors and (vii) RIZAPORT® (RHB-103) - an oral thin film formulation of rizatriptan for acute migraines, with a U.S. NDA currently under discussion with the FDA and marketing authorization received in two EU member states under the European Decentralized Procedure (DCP). More information about the Company is available at: www.redhillbio.com. 1 The poster was authored by Ira N. Kalfus, MD, Medical Director, RedHill Biopharma; Gilead Raday, Chief Operating Officer, RedHill Biopharma; Reza Fathi, PhD, Senior VP R&D, RedHill Biopharma and David Y. Graham, MD, Professor of Medicine, Molecular Virology and Microbiology, Baylor College of Medicine. This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Such statements may be preceded by the words “intends,” “may,” “will,” “plans,” “expects,” “anticipates,” “projects,” “predicts,” “estimates,” “aims,” “believes,” “hopes,” “potential” or similar words. Forward-looking statements are based on certain assumptions and are subject to various known and unknown risks and uncertainties, many of which are beyond the Company’s control, and cannot be predicted or quantified and consequently, actual results may differ materially from those expressed or implied by such forward-looking statements. Such risks and uncertainties include, without limitation, risks and uncertainties associated with (i) the initiation, timing, progress and results of the Company’s research, manufacturing, preclinical studies, clinical trials, and other therapeutic candidate development efforts; (ii) the Company’s ability to advance its therapeutic candidates into clinical trials or to successfully complete its preclinical studies or clinical trials; (iii) the extent and number of additional studies that the Company may be required to conduct and the Company’s receipt of regulatory approvals for its therapeutic candidates, and the timing of other regulatory filings, approvals and feedback; (iv) the manufacturing, clinical development, commercialization, and market acceptance of the Company’s therapeutic candidates; (v) the Company’s ability to successfully market Donnatal® and EnteraGam®, (vi) the Company’s ability to establish and maintain corporate collaborations; (vii) the Company's ability to acquire products approved for marketing in the U.S. that achieve commercial success and build its own marketing and commercialization capabilities; (viii) the interpretation of the properties and characteristics of the Company’s therapeutic candidates and of the results obtained with its therapeutic candidates in research, preclinical studies or clinical trials; (ix) the implementation of the Company’s business model, strategic plans for its business and therapeutic candidates; (x) the scope of protection the Company is able to establish and maintain for intellectual property rights covering its therapeutic candidates and its ability to operate its business without infringing the intellectual property rights of others; (xi) parties from whom the Company licenses its intellectual property defaulting in their obligations to the Company; and (xii) estimates of the Company’s expenses, future revenues capital requirements and the Company’s needs for additional financing; (xiii) competitive companies and technologies within the Company’s industry. More detailed information about the Company and the risk factors that may affect the realization of forward-looking statements is set forth in the Company's filings with the Securities and Exchange Commission (SEC), including the Company's Annual Report on Form 20-F filed with the SEC on February 23, 2017. All forward-looking statements included in this Press Release are made only as of the date of this Press Release. We assume no obligation to update any written or oral forward-looking statement unless required by law.


News Article | November 18, 2016
Site: www.eurekalert.org

HOUSTON -- (Nov. 18, 2016) -- Scientists from Rice University, Baylor College of Medicine and other institutions are using synthetic biology to capture elusive, short-lived snippets of DNA that healthy cells produce on their way to becoming cancerous. Researchers said the work could lead to the development of new drugs that could prevent cancer by neutralizing "DNA intermediates," key pieces of genetic code that are produced when healthy cells become cancerous. The research is described in a new paper in the open-access journal Science Advances. "In my lab we study how the genome -- the genes in an organism -- changes, in particular, how the genome of normal cells changes to transform the cells into cancerous cells," said project lead scientist Susan Rosenberg, Baylor's Ben F. Love Chair in Cancer Research and the leader of the Cancer Evolvability Program at Baylor's Dan L Duncan Comprehensive Cancer Center. When cells divide and make copies of the instructions encoded in their DNA, the DNA unwinds and becomes vulnerable to damage that must be repaired. Sometimes the process of repairing the DNA can also cause mutations and errors. When these errors accumulate, the cells may acquire characteristics of cancer. "The process of editing the DNA is carried out by specific enzymes -- proteins that work on DNA to fix the mistakes," said Rosenberg, who is also an adjunct professor in Rice's Department of BioSciences. She said DNA repair usually takes several steps to complete. Between the original DNA and the final product, cells produce DNA reaction intermediates, which are crucial to the reaction but are difficult to study because they are present for just a fraction of a second as an enzyme catalyzes the changing of one molecule into another. "The intermediate molecules are the most important parts of biochemical reactions," said Rosenberg, who holds appointments in Baylor's departments of Molecular and Human Genetics, Molecular Virology and Microbiology, and Biochemistry and Molecular Biology. "They define what the reaction is and how it will proceed. But because they are transient and elusive, it's really difficult to study them, especially in living cells. We wanted to do that. We decided to invent synthetic proteins that would trap DNA reaction intermediates in living cells." Qian Mei, a graduate student in Rice's Systems, Synthetic and Physical Biology program and a research assistant in the Rosenberg lab, took on the task of applying the synthetic protein that could capture the short-lived intermediates. Using the tools of synthetic biology, Rosenberg and colleagues created and added packages of genes to Escherichia coli, an organism that Rosenberg's group and others have shown to be a reliable model of the genetic changes that occur in animal cells. Rosenberg said other investigators also have attempted to trap intermediates, but they have only succeeded in a few biochemical reactions. "We want to use synthetic proteins to study mechanisms that change DNA sequence," she said. "We do that now with genetics and genomics in my lab. But genomics, which allows us to compare the genes of normal cells with those of cancerous cells, is like reading the fossil record of these processes. We want to see how the real-time processes that change DNA happen, including all the intermediate steps, which our synthetic proteins allow us to freeze in time and isolate." In their tests on , Mei, Rosenberg and colleagues from Baylor, the University of Texas at Austin and the University of Texas MD Anderson Cancer Center found they could discover molecular mechanisms underlying genome instability, a hallmark of cancer. In one instance, they discovered a new role for an protein that is related to five human cancer proteins. They then analyzed gene-expression data from human cancers and were able to implicate two of the five -related human cancer proteins in potentially promoting cancer by a similar mechanism -- one not previously implicated. "The most exciting part in this paper for me is that we can learn something new about the mechanisms of cancer from the model," said Mei, co-first author of the new paper. "Even though bacteria and human cells are very different, many DNA repair proteins are highly conserved through evolution; this makes a good model to study how cells repair DNA or accumulate mutations." Rosenberg and colleagues think that their approach offers significant advantages. For instance, with the synthetic proteins, they have been able to identify specific DNA-repair intermediate molecules, their numbers in cells, rates of formation and locations in the genome and the molecular reactions in which they participate. "It is most exciting that we are now able to trap, map and quantify transient DNA reaction intermediates in single living cells," said co-first author Jun Xia, graduate student in the Rosenberg lab and in the Integrative Molecular and Biomedical Sciences program at Baylor. "This new technology helps us reveal the origins of genome instability." "When you know these reactions and the role each intermediate plays in the mechanisms that change DNA, you can think about making drugs that will stop them," Rosenberg said. "In the future, we hope we will be able to design drugs that target specific types of cancers -- drugs that block the cells' ability to evolve into cancer cells, instead of, or in addition to, traditional chemotherapies that kill or stop cancer cells from growing." Other contributors to the work include Li-Tzu Chen, Chien-Hui Ma, Jennifer Halliday, Hsin-Yu Lin, David Magnan, John Pribis, Devon Fitzgerald, Holly Hamilton, Megan Richters, Ralf Nehring, Xi Shen, Lei Li, David Bates, P.J. Hastings, Christophe Herman and Makkuni Jayaram. The research was supported by the WM Keck Foundation, the National Institutes of Health, NASA, the Cancer Prevention and Research Institute of Texas, the National Science Foundation, the Welch Foundation, Baylor College of Medicine, the Dan L Duncan Comprehensive Cancer Center and the John S. Dunn Gulf Coast Consortium for Chemical Genomics. VIDEO is available at: High-resolution IMAGES are available for download at: CAPTION: (From left) Baylor College of Medicine's Susan Rosenberg discusses research aimed at capturing elusive, short-lived "DNA intermediates," key pieces of genetic code that are produced when healthy cells become cancerous, with Baylor graduate student Jun Xia and Rice University graduate student Qian Mei, who are co-first authors on a new paper about the work in Science Advances. (Photo courtesy of Baylor College of Medicine) CAPTION: The orange wheel shows the circular chromosome or genome of bacteria. The spikes indicate where a molecular intermediate in DNA repair -- four-way DNA junctions -- accumulate near a reparable double strand break in the genome. (Image courtesy of Jun Xia and Qian Mei) The DOI of the Science Advances paper is: 10.1126/sciadv.1601605 A copy of the paper is available at: http://advances. This release can be found online at news.rice.edu. Located on a 300-acre forested campus in Houston, Rice University is consistently ranked among the nation's top 20 universities by U.S. News & World Report. Rice has highly respected schools of Architecture, Business, Continuing Studies, Engineering, Humanities, Music, Natural Sciences and Social Sciences and is home to the Baker Institute for Public Policy. With 3,910 undergraduates and 2,809 graduate students, Rice's undergraduate student-to-faculty ratio is 6-to-1. Its residential college system builds close-knit communities and lifelong friendships, just one reason why Rice is ranked No. 1 for happiest students and for lots of race/class interaction by the Princeton Review. Rice is also rated as a best value among private universities by Kiplinger's Personal Finance. To read "What they're saying about Rice," go to http://tinyurl. .


News Article | November 22, 2016
Site: www.rdmag.com

Scientists from Rice University, Baylor College of Medicine and other institutions are using synthetic biology to capture elusive, short-lived snippets of DNA that healthy cells produce on their way to becoming cancerous. Researchers said the work could lead to the development of new drugs that could prevent cancer by neutralizing "DNA intermediates," key pieces of genetic code that are produced when healthy cells become cancerous. The research is described in a new paper in the open-access journal Science Advances. "In my lab we study how the genome -- the genes in an organism -- changes, in particular, how the genome of normal cells changes to transform the cells into cancerous cells," said project lead scientist Susan Rosenberg, Baylor's Ben F. Love Chair in Cancer Research and the leader of the Cancer Evolvability Program at Baylor's Dan L Duncan Comprehensive Cancer Center. When cells divide and make copies of the instructions encoded in their DNA, the DNA unwinds and becomes vulnerable to damage that must be repaired. Sometimes the process of repairing the DNA can also cause mutations and errors. When these errors accumulate, the cells may acquire characteristics of cancer. "The process of editing the DNA is carried out by specific enzymes -- proteins that work on DNA to fix the mistakes," said Rosenberg, who is also an adjunct professor in Rice's Department of BioSciences. She said DNA repair usually takes several steps to complete. Between the original DNA and the final product, cells produce DNA reaction intermediates, which are crucial to the reaction but are difficult to study because they are present for just a fraction of a second as an enzyme catalyzes the changing of one molecule into another. "The intermediate molecules are the most important parts of biochemical reactions," said Rosenberg, who holds appointments in Baylor's departments of Molecular and Human Genetics, Molecular Virology and Microbiology, and Biochemistry and Molecular Biology. "They define what the reaction is and how it will proceed. But because they are transient and elusive, it's really difficult to study them, especially in living cells. We wanted to do that. We decided to invent synthetic proteins that would trap DNA reaction intermediates in living cells." Qian Mei, a graduate student in Rice's Systems, Synthetic and Physical Biology program and a research assistant in the Rosenberg lab, took on the task of applying the synthetic protein that could capture the short-lived intermediates. Using the tools of synthetic biology, Rosenberg and colleagues created and added packages of genes to Escherichia coli, an organism that Rosenberg's group and others have shown to be a reliable model of the genetic changes that occur in animal cells. Rosenberg said other investigators also have attempted to trap intermediates, but they have only succeeded in a few biochemical reactions. "We want to use synthetic proteins to study mechanisms that change DNA sequence," she said. "We do that now with genetics and genomics in my lab. But genomics, which allows us to compare the genes of normal cells with those of cancerous cells, is like reading the fossil record of these processes. We want to see how the real-time processes that change DNA happen, including all the intermediate steps, which our synthetic proteins allow us to freeze in time and isolate." In their tests on , Mei, Rosenberg and colleagues from Baylor, the University of Texas at Austin and the University of Texas MD Anderson Cancer Center found they could discover molecular mechanisms underlying genome instability, a hallmark of cancer. In one instance, they discovered a new role for an protein that is related to five human cancer proteins. They then analyzed gene-expression data from human cancers and were able to implicate two of the five -related human cancer proteins in potentially promoting cancer by a similar mechanism -- one not previously implicated. "The most exciting part in this paper for me is that we can learn something new about the mechanisms of cancer from the model," said Mei, co-first author of the new paper. "Even though bacteria and human cells are very different, many DNA repair proteins are highly conserved through evolution; this makes a good model to study how cells repair DNA or accumulate mutations." Rosenberg and colleagues think that their approach offers significant advantages. For instance, with the synthetic proteins, they have been able to identify specific DNA-repair intermediate molecules, their numbers in cells, rates of formation and locations in the genome and the molecular reactions in which they participate. "It is most exciting that we are now able to trap, map and quantify transient DNA reaction intermediates in single living cells," said co-first author Jun Xia, graduate student in the Rosenberg lab and in the Integrative Molecular and Biomedical Sciences program at Baylor. "This new technology helps us reveal the origins of genome instability." "When you know these reactions and the role each intermediate plays in the mechanisms that change DNA, you can think about making drugs that will stop them," Rosenberg said. "In the future, we hope we will be able to design drugs that target specific types of cancers -- drugs that block the cells' ability to evolve into cancer cells, instead of, or in addition to, traditional chemotherapies that kill or stop cancer cells from growing."


News Article | September 20, 2016
Site: www.biosciencetechnology.com

A team of scientists from Baylor College of Medicine and Vanderbilt University Medical Center have determined a mechanism by which human antibodies target and block noroviruses. Their study, which appears in the Proceedings of the National Academy of Sciences, opens the possibility of developing therapeutic agents against this virus that causes the death of about 200,000 children every year. "Some people infected with norovirus do not get sick," said senior author Dr. B V Venkataram Prasad, professor of virology and the Alvin Romansky Chair in biochemistry at Baylor. "We wanted to understand how these protective human antibodies work." The researchers screened and isolated protective antibodies from human blood and discovered that the most protective were of the IgA type, an antibody mostly involved in gut immunity. According to the Centers for Disease Control and Prevention, norovirus is the leading cause of foodborne illness and of acute gastroenteritis in all age groups in the U.S. The virus enters the body hidden in contaminated food, travels through the digestive system and infects the top layer of cells, the epithelial cells, on the small intestine. To enter the epithelial cells the virus attaches to complex sugar molecules, or glycans, on the surface of the cells. "The initial attachment is very important for the virus to subsequently get in," said Prasad. "It is like knocking at the door, and then the door opens and the virus can get inside the cells." The epithelial cells have a thick cover of glycans of diverse types, but norovirus seems to selectively bind to a particular group of glycans, the histo-blood group antigens, or HBGA, which also determine our blood types. Different strains of norovirus interact with different types of HBGAs. "The site on the norovirus particles that binds to HBGA is located in a region of the virus called P domain," said Prasad. "We knew that human antibodies that bind to P domain of norovirus and block HBGA binding correlate with protection, but we didn't know where these antibodies bind on the P domain and how this interaction prevents norovirus from binding to HBGA. Do the antibodies change the structure of the P domain or disrupt the HBGA binding site so it can no longer bind to the glycans? Or do the antibodies physically block the glycan binding site on P domain preventing its binding to HBGAs? We answered these questions with X-ray crystallographic analysis." Scientists use X-ray crystallography to determine the three-dimensional structure of highly purified molecules in the form of crystals. Crystals are symmetrical structures that produce symmetrical diffraction patterns when irradiated with X rays. Scientists use the symmetrical X-ray diffraction patterns to determine how molecules would look in 3-D. "The hardest, most time-consuming part of this project was to obtain good quality diffracting crystals ready for X-ray crystallographic analysis," said first author Dr. Sreejesh Shanker, a senior scientist in the Prasad lab. To answer the question of how the antibodies prevent norovirus from binding to HBGA, Shanker purified the complex of the norovirus P domain with the part of the antibody that binds to the domain, called antigen binding fragment (Fab), of a human IgA antibody. He then successfully used X-ray crystallography to determine the structure of the complex. "We found that the Fab fragment binds close to the HBGA binding site. It does not change the structure of the HBGA binding site, but physically blocks access to the site," said Shanker. These results open the possibility of developing compounds that mimic the structure of the Fab fragment and using them as a therapeutic agent to block the virus binding to cells," said Prasad. Now that the scientific community has the ability to grow noroviruses in the lab (Science, 2016), it is possible to test whether blocking binding would inhibit infection and replication of the virus inside the cells. "We see the possibility of using these blocking therapeutic agents to treat norovirus infections in transplant recipients suffering from these infections, which can be fatal," said co-senior author Dr. Mary Estes, Cullen Endowed Professor of Human and Molecular Virology and Microbiology at Baylor and emeritus founding director of the Texas Medical Center Digestive Diseases Center.


News Article | November 4, 2016
Site: www.rdmag.com

A pair of studies have suggested that the Ebola virus outbreak that began in 2013 may have gained a genetic mutation that appears to have helped it better target human cells. On Nov. 3, a study from the University of Nottingham and a second study conducted by the co-led by scientists at The Scripps Research Institute (TSRI), the University of Massachusetts Medical School, the Broad Institute of the Massachusetts Institute of Technology and Harvard University was published in Cell that conclude that the Ebola virus actually grew in strength as the outbreak started to spread. “There was this belief that Ebola virus essentially never changes,” said TSRI infectious disease researcher Kristian Andersen, who also serves as director of infectious disease genomics at the Scripps Translational Science Institute (STSI), in a statement. “But this study tells us that a natural mutation in Ebola virus—which occurred during an outbreak—changed infectivity of human cells.” In the Scripps study Andersen and his team used a sequence catalog of viral genomes previously generated from 1,438 of the mora than 28,000 Ebola cases during the recent outbreak, a much larger sample size than ever studied on Ebola before. During this research they discovered a mutation on a site on Ebola’s outer protein—called glycoprotein—that binds to its receptor on host cells, meaning that mutations in that site can affect a virus’s ability to infect. “This receptor binding domain of the virus has been the same since the first Ebola outbreak in 1976,” said Andersen. “This is the only time we’ve ever seen a mutation in this domain.” The researchers found that the version of Ebola carrying the mutation, being dubbed GP-A82V, caused about 90 percent of the infections in the recent outbreak The scientists then tested the mutation’s reaction to many types of animal cells, which proved the mutation specifically helps the virus infect primate cells. It is believed that Ebola normally lives in bats, but the virus had more opportunities to adapt to humans with more human hosts. However, questions still remain for researchers, including how the mutation actually boost the virus’s ability to enter human cells. One hypothesis is that the mutation shifts nearby amino acids in the Ebola receptor binding domain, helping the glycoprotein better fit with the human host receptor. Scientists in the Nottingham study infected human liver cells grown in a test tube with pseudoviruses containing different mutant surface proteins, which proved that the number of genetic changes that occurred during the outbreak increased infectivity. “I think our study reminds us that if you take a virus and allow it to infect a new host for a considerable amount of time, eventually it may acquire a set of mutations that will benefit it, for example increasing its ability to spread or changing the disease that it causes,” Jonathan Ball, Professor of Molecular Virology at the University of Nottingham, and one of the authors of the study said in a statement. “In order to be prepared we need to know whether similar things are occurring in other outbreaks such as the ongoing Zika and MERS-coronavirus epidemics.” Andersen also said there is a chance the GP-A82V form of Ebola is no longer a threat, but research is important because it answers questions as to whether the Ebola virus can gain mutations during outbreaks that can potentially change the function of viral proteins. “It’s important to understand that once the outbreak is over, this particular virus will likely disappear,” Andersen said. The scientists will now examine other mutations that recently showed up and to see if increased infectivity changes mortality rates and the likelihood of a person transmitting the disease.

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