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| Guelph scientists develop first vaccine to help control autism symptoms Posted: 23 Apr 2013 09:00 PM PDT A first-ever vaccine created by University of Guelph researchers for gut bacteria common in autistic children may also help control some autism symptoms. The groundbreaking study by Brittany Pequegnat and Guelph chemistry professor Mario Monteiro appears this month in the journal Vaccine.
They developed a carbohydrate-based vaccine against the gut bug, Clostridium bolteae. C. bolteae is known to play a role in gastrointestinal disorders, and it often shows up in higher numbers in the GI tracts of autistic children than in those of healthy kids. More than 90 per cent of children with autism spectrum disorders suffer from chronic, severe gastrointestinal symptoms. Of those, about 75 per cent suffer from diarrhea, according to current literature. “Little is known about the factors that predispose autistic children to C. bolteae,” said Monteiro. Although most infections are handled by some antibiotics, he said, a vaccine would improve current treatment. “This is the first vaccine designed to control constipation and diarrhea caused by C. bolteae and perhaps control autism-related symptoms associated with this microbe,” he said. Autism cases have increased almost sixfold over the past 20 years, and scientists don’t know why. Although many experts point to environmental factors, others have focused on the human gut. Some researchers believe toxins and/or metabolites produced by gut bacteria, including C. bolteae, may be associated with symptoms and severity of autism, especially regressive autism. Pequegnat, a master’s student, and Monteiro used bacteria grown by Mike Toth, a Guelph PhD student in the lab of microbiology professor Emma Allen-Vercoe. The new anti- C. bolteae vaccine targets the specific complex polysaccharides, or carbohydrates, on the surface of the bug. The vaccine effectively raised C. bolteae-specific antibodies in rabbits. Doctors could also use the vaccine induced antibodies to quickly detect the bug in a clinical setting, said Monteiro. The vaccine might take more than 10 years to work through pre-clinical and human trials, and it may take even longer before a drug is ready for market, Monteiro said. “But this is a significant first step in the design of a multivalent vaccine against several autism-related gut bacteria,” he said. Monteiro has studied sugar-based vaccines for two other gastric pathogens: Campylobacter jejuni, which causes travellers’ diarrhea, and Clostridium difficile, which causes antibiotic-associated diarrhea. ### The research was supported by the Natural Sciences and Engineering Research Council. Contact: Prof. Mario Monteiro |
| Drug therapy offers high cure rate for 2 hepatitis C subtypes Posted: 22 Apr 2013 09:00 PM PDT A new drug is offering dramatic cure rates for hepatitis C patients with two subtypes of the infection — genotype 2 and 3, say a team of scientists led by Weill Cornell Medical College researchers. These two subtypes account for approximately 25 percent of hepatitis C infection in the United States.
The drug, called sofosbuvir, offers more effective treatment for most patients studied in a Phase 3 clinical trial who had no other treatment options, report researchers in The New England Journal of Medicine. After three months of combined therapy with sofosbuvir and the antiviral drug ribavirin, the patient response rate for those with genotype 2 was 93 percent, and 61 percent in patients with genotype 3. This new study is one of several testing new hepatitis C drugs that were published April 23 in an online edition of NEJM. The journal publication coincides with the International Liver Congress 2013 in Amsterdam, the Netherlands, where the results also will be presented. “The new sofosbuvir therapy offers a much-needed alternative to standard therapy with interferon, which can cause significant side effects for hepatitis C patients,” says the study’s lead investigator, Dr. Ira Jacobson, chief of the Division of Gastroenterology and Hepatology and Vincent Astor Distinguished Professor of Medicine at Weill Cornell Medical College. “We have dreamed for years of being able to eliminate interferon from our hepatitis C regimens and this study is one of several that are finally bringing us very close to realizing that goal,” says Dr. Jacobson, who is also a gastroenterologist at the Center for Advanced Digestive Care at New York-Presbyterian Hospital/Weill Cornell Medical Center and medical director of the Center for the Study of Hepatitis C, a collaboration between Weill Cornell, NewYork-Presbyterian/Weill Cornell and The Rockefeller University. The 207 patients enrolled in the clinical trial, known as POSITRON, either did not respond to interferon, could not tolerate it or were unwilling to use it, despite the fact that there were no other treatment options available to them. “This new treatment represents a paradigm shift in the way that hepatitis C is going to be treated,” says Dr. Jacobson. “We are achieving the same or higher cure rates in many patients with sofosbuvir, compared to interferon, and we are doing it in half the time with a drug that has a remarkable safety profile.” Dr. Jacobson estimates that up to half of patients with hepatitis C infection either can’t use interferon or don’t want to use it. “Sofosbuvir is an extremely promising treatment for this population. It is widely hoped that combinations of potent antiviral drugs will eventually replace the use of interferon, in general, for most hepatitis C patients.” The drug sofosbuvir works by interfering with the ability of the hepatitis C virus to replicate. The drug also confers a high barrier to developing the complication of drug resistance. The U.S. Food and Drug Administration (FDA) has not yet approved sofosbuvir. However, results of the four clinical trials published in the NEJM were used to support the regulatory filing submitted to the FDA by the drug’s developer, Gilead Sciences, Inc. No Treatment Options for Many Patients Approximately 170 million people are infected with hepatitis C worldwide and 350,000 people die each year from the disease. According to federal statistics, there are an estimated four million people in the U.S. infected with hepatitis C. As there are often no symptoms, most people with hepatitis C are unaware that they are infected. When left untreated, hepatitis C virus can cause progressive liver disease such as cirrhosis, liver cancer and liver failure. The virus is spread by contact with infected blood, such as through blood transfusions, injection drug use or sexual contact. There are seven major genotypes of hepatitis C, but most cases are 1, 2 or 3. Genotype 1 is the most common subtype in the U.S. Genotypes 2 and 3 are more common in Europe than in the U.S. and genotype 3 is very prevalent on the Indian subcontinent. In the study, three-fourths of participants (207) were randomized to treatment with sofosbuvir and ribavirin while one-fourth (71) of participants were randomized to a placebo treatment. All of the patients either did not respond to interferon, or did not want to use it. “This mirrors what happens frequently in the clinic,” says Dr. Jacobson. “Between 15 and 30 percent of patients with hepatitis C genotype 2 or 3 infections do not have a response to interferon therapy and do not have alternate treatment options.” Patients were enrolled internationally at 63 sites in the United States, Canada, Australia and New Zealand. Study results show the response rate for all treated patients with sofosbuvir was 78 percent compared to 0 percent in participants treated with placebo agents. Patients with genotype 2 had a higher cure rate (93 percent) than those with genotype 3 (61 percent), and patients without cirrhosis had a higher response rate (81 percent) compared with participants diagnosed with cirrhosis (61 percent). The results of another clinical trial, led by Dr. David R. Nelson of the University of Florida at Gainesville, were incorporated into this NEJM manuscript publication. This clinical trial study, called FUSION, was designed to test sofosbuvir and ribavirin in hepatitis C patients with genotype 2 or 3 who had failed interferon therapy. In FUSION, the drug regimen was tested for both 12 and 16 weeks in patients with genotype 2 or 3. The findings showed that extended use of sofosbuvir resulted in a higher cure rate in both genotypes, but that the difference seen in genotype 3 was highly significant. For genotype 2, 12 versus 16 weeks of treatment resulted in response rates of 86 percent compared to 94 percent; and for genotype 3, the response rates were 30 percent versus 62 percent, respectively. “Given the absence to date of alternative therapies for patients with genotype 2 or 3 who have failed interferon therapy or for whom it is not an option, treatment with the new sofosbuvir regimen offers a vast improvement,” Dr. Jacobson says. “But the optimal duration of treatment for genotype 3 patients, in order to maximize their chance of cure, remains undefined. It could be longer than 16 weeks.” Dr. Jacobson adds that future clinical studies will continue to define the optimal length of treatment duration for patients with genotype 3, and that other antiviral drugs in combination with sofosbuvir might shorten the duration of treatment needed to maximize the rates of response. ### Both the POSITRON and FUSION studies were funded by Gilead Sciences. Another paper in the same edition of the NEJM reports two additional studies of sofosbuvir-containing therapy, one evaluating a 12 week regimen of peginterferon, ribavirin and sofosbuvir in patients with genotypes 1, 4, 5 and 6 who have never been treated before; the other reporting results of a trial comparing 24 weeks of peginterferon and ribavin with 12 weeks of sofosbuvir and ribavirin in treatment naïve patients with genotypes 2 and 3. Dr. Jacobson is a consultant, lecturer and a funded research investigator for Gilead Sciences. As medical director of the collaborative Center for the Study of Hepatitis C at Weill Cornell, NewYork-Presbyterian/Weill Cornell and Rockefeller, Dr. Jacobson’s research has long been funded by Maurice R. Greenberg, The Starr Foundation and the Greenberg Medical Research Institute. The Center, founded in 2000, is the only comprehensive, multidisciplinary center dedicated to the study of hepatitis C and hepatic disease in the New York tri-state area. The study co-authors include Dr. Stuart C. Gordon from Henry Ford Health Systems, Detroit, Mich,; Dr. Kris V. Kowdley from Virginia Mason Medical Center, Seattle, Wash.; Dr. Eric M. Yoshida from University of British Columbia, Vancouver, Canada; Dr. Jordan Feld from the University of Toronto, Canada; Dr. Maribel Rodriguez-Torres of Fundacion de Investigacion, San Juan, Puerto Rico; Dr. Mark S. Sulkowski from Johns Hopkins University School of Medicine, Baltimore, Md.; Dr. Mitchell L. Shiffman from the Liver Institute of Virginia, Bon Secours Hampton Roads Health System, Newport News, Va.; Dr. Eric Lawitz from University of Texas Health Science Center, San Antonio, Texas; Dr. M. Tarek Al-Assi from Texas Digestive Disease Consultants, Arlington, Texas; Dr. Gregory Everson from University of Colorado Denver, Aurora, Colo.; Dr. Michael Bennett from Medical Associates Research Group, San Diego, Calif.; Dr. Eugene Schiff from the University of Miami, Miami, Fla.; Dr. Keyur Patel of Duke University, Durham, N.C.; Dr. Stephen Pianko of Monash Medical Centre and Monash University, Melbourne, Australia; and Dr. G. Mani Subramanian, Dr. Di An, Dr. Ming Lin, Dr. John McNally, Dr. Diana Brainard, Dr. William T. Symonds and Dr. John G. McHutchison from Gilead Sciences, in Foster City, Calif. Weill Cornell Medical College
Weill Cornell Medical College, Cornell University’s medical school located in New York City, is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research from bench to bedside, aimed at unlocking mysteries of the human body in health and sickness and toward developing new treatments and prevention strategies. In its commitment to global health and education, Weill Cornell has a strong presence in places such as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. Through the historic Weill Cornell Medical College in Qatar, the Medical College is the first in the U.S. to offer its M.D. degree overseas. Weill Cornell is the birthplace of many medical advances — including the development of the Pap test for cervical cancer, the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial of gene therapy for Parkinson’s disease, and most recently, the world’s first successful use of deep brain stimulation to treat a minimally conscious brain-injured patient. Weill Cornell Medical College is affiliated with NewYork-Presbyterian Hospital, where its faculty provides comprehensive patient care at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. The Medical College is also affiliated with the Methodist Hospital in Houston. For more information, visit weill.cornell.edu. Contact: Lauren Woods |
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