Cancer drug Might Be a Possible Cure for Hepatitis B

MELBOURNE, AUSTRALIA – Scientists have found a potential cure for hepatitis B virus (HBV) infections, with a promising new treatment proving 100 per cent successful in eliminating the infection in preclinical models.

Australian patients are now the first in the world to have access to the potential treatment – a combination of an antiviral drug and an anti-cancer drug – which is in phase 1/2a clinical trials in Melbourne, Perth and Adelaide.

Walter and Eliza Hall Institute

Scientists from Melbourne’s Walter and Eliza Hall Institute developed the combination treatment using birinapant, a drug developed by US biotech company TetraLogic Pharmaceuticals for treating cancer. Hepatitis B is a chronic viral disease that is currently incurable.

Dr Marc Pellegrini, Dr Greg Ebert and colleagues at the institute used their studies of the behaviour of hepatitis B virus in infected cells as a basis for the treatment. The research was published today in two papers in the journal Proceedings of the National Academy of Sciences.

Dr Pellegrini said the treatment was successful in curing infections in preclinical models, leading to a human trial that began in December 2014. “We were 100 per cent successful in curing HBV infection in hundreds of tests in preclinical models,” Dr Pellegrini said.

“Birinapant enabled the destruction of hepatitis B-infected liver cells while leaving normal cells unharmed. Excitingly, when birinapant was administered in combination with current antiviral drug entecavir, the infection was cleared twice as fast compared with birinapant alone. We are hopeful these promising results will be as successful in human clinical trials, which are currently underway in Melbourne, Perth and Adelaide.”

The combination treatment, developed in collaboration with TetraLogic Pharmaceuticals based in Malvern, Pennsylvania, US, targets the cell signalling pathways that the hepatitis B virus uses to keep host liver cells alive.

Chronic infectious diseases such as HBV live within the host’s cells, enabling them to persist within the body for many months or years, Dr Pellegrini said.

“Normally, liver cells would respond to infection by switching on a signal that tells the cell to destroy itself ‘for the greater good’, preventing further infection,” he said. “However our research showed that the virus commandeers the liver cells’ internal communications, telling the cells to ignore the infection and stay alive. Birinapant flips the cell survival ‘switch’ used by the virus, causing the infected cell to die.”

More than two billion people worldwide are infected with hepatitis B and approximately 400 million have a chronic HBV infection. The virus infects liver cells and can lead to complications including cirrhosis and liver cancer, resulting in more than 780,000 deaths annually.

Treatments that enable the host cell to rid itself of the virus, rather than targeting the virus itself, may prevent drug-resistant strains of HBV emerging, Dr Pellegrini said. “It is relatively easy for an organism to adapt to a drug, but it is very difficult to adapt to a change in the host cell,” he said. “The virus relies on the survival mechanisms of the host, so if it can’t exploit them, it dies. Such a monumental change in the virus’ environment may be too big a hurdle for it to adapt to.”

Dr Pellegrini and colleagues will now investigate if the same strategy could be applied to other chronic infectious diseases. “Pathogens that infect and reside inside host cells, including viral diseases such as HIV, herpes simplex and dengue fever, and bacterial infections such as tuberculosis, could all potentially be cured in a similar way,” he said.

Patients are currently being recruited for the clinical trial in Melbourne by Nucleus Network, situated at the Alfred Hospital; in Perth by Linear Clinical Research, located at Sir Charles Gardiner Hospital; and in Adelaide by IDT CMAX, situated at the Royal Adelaide Hospital.

- MFP News Services
- 5/22/15

Gestational Diabetes Maybe Associated With Greater Risk of Autism in Children

PASADENA, Calif., — Children whose mothers developed gestational diabetes by the 26th week of pregnancy were at increased risk of developing autism later in life, according to a new Kaiser Permanente study published recently in the Journal of the American Medical Association.

Researchers examined the electronic health records of more than 322,000 ethnically diverse children born between 28 and 44 weeks at Kaiser Permanente Southern California medical centers between January 1995 and December 2009. They followed the children for an average of 5.5 years and found that those exposed to gestational diabetes by the 26th week of pregnancy had a 63 percent increased risk of being diagnosed with an autism spectrum disorder than children who were not exposed. After taking into account maternal age, education, race and ethnicity, household income and other factors, the increased risk of autism associated with gestational diabetes was 42 percent.

Kaiser Permanente - Division of Research

“The exposure of fetuses to maternal hyperglycemia may have long-lasting effects on organ development and function, but whether this can disrupt fetal brain development and heighten risk for neurobehavioral developmental disorders in offspring is less clear,” said study lead author Anny H. Xiang, PhD, of the Kaiser Permanente Southern California Department of Research & Evaluation. “Future studies should address whether early diagnosis and treatment of gestational diabetes can reduce the risk of autism.” She noted that this was an observational study, therefore the findings reveal associations between gestational diabetes and risk of a child developing autism rather than proving a cause and effect relationship.

The study also found that children whose mothers developed gestational diabetes after 26 weeks of pregnancy had no more risk of autism spectrum disorder than children whose mothers did not have preexisting diabetes or gestational diabetes.

“If the findings of this study reflect a cause and effect relationship, then they add another factor to a growing list of risks associated with gestational diabetes,” said study co-author Edward S. Curry, MD, pediatric learning and behavior specialist, Kaiser Permanente Fontana Medical Center. “Our study findings also suggest that early screening for autism in children of women with gestational diabetes diagnosed by 26 weeks gestation may be warranted.”

Autism spectrum disorder is a group of developmental disabilities that can cause significant social, communication and behavioral challenges, according to the Centers for Disease Control and Prevention. People with autism spectrum disorders may communicate, interact, behave and learn in ways that are different from other people and can range from gifted to severely challenged. About 1 in 68 children have been identified with autism spectrum disorder, according to estimates from CDC’s Autism and Developmental Disabilities Monitoring Network.

Gestational diabetes is a type of diabetes that develops or is first recognized during pregnancy. While the true prevalence of gestational diabetes is unknown and varies based on diagnostic criteria used, a recent study from the CDC indicated that rates could be as high as 9.2 percent. Gestational diabetes can also lead to additional health problems for the mother, including an increased risk of developing type 2 diabetes and a greater likelihood of delivering a large baby.

- MFP News Services
- 5/13/15

New Potential Cause for Alzheimer’s Discovered

DURHAM, N.C. — Increasingly, evidence supports the idea that the immune system, which protects our bodies from foreign invaders, plays a part in Alzheimer’s disease. But the exact role of immunity in the disease is still a mystery.

A new Duke University study in mice suggests that in Alzheimer’s disease, certain immune cells that normally protect the brain begin to abnormally consume an important nutrient: arginine. Blocking this process with a small-molecule drug prevented the characteristic brain plaques and memory loss in a mouse model of the disease.

Published recently in the Journal of Neuroscience, the new research not only points to a new potential cause of Alzheimer’s but also may eventually lead to a new treatment strategy.

“If indeed arginine consumption is so important to the disease process, maybe we could block it and reverse the disease,” said senior author Carol Colton, professor of neurology at the Duke University School of Medicine, and a member of the Duke Institute for Brain Sciences.

The brains of people with Alzheimer’s disease show two hallmarks — ‘plaques’ and ‘tangles’ — that researchers have puzzled over for some time. Plaques are the build up of sticky proteins called beta amyloid, and tangles are twisted strands of a protein called tau.

In the study, the scientists used a type of mouse, called CVN-AD, that they had created several years ago by swapping out a handful of important genes to make the animal’s immune system more similar to a human’s.

Compared with other mice used in Alzheimer’s research, the CVN-AD mouse has it all: plaques and tangles, behavior changes, and neuron loss.

In addition, the gradual onset of these symptoms in the CVN-AD mouse gave researchers a chance to study its brain over time and to focus on how the disease begins, said the study’s first author Matthew Kan, an MD/PhD student in Colton’s lab.

Looking for immune abnormalities throughout the lifespan of the mice, the group found that most immune system components stayed the same in number, but a type of brain-resident immune cells called microglia that are known first responders to infection begin to divide and change early in the disease.

The microglia express a molecule, CD11c, on their surface. Isolating these cells and analyzing their patterns of gene activity, the scientists found heightened expression of genes associated with suppression of the immune system. They also found dampened expression of genes that work to ramp up the immune system.

“It’s surprising, because [suppression of the immune system is] not what the field has been thinking is happening in AD,” Kan said. Instead, scientists have previously assumed that the brain releases molecules involved in ramping up the immune system, that supposedly damage the brain.

The group did find CD11c microglia and arginase, an enzyme that breaks down arginine, are highly expressed in regions of the brain involved in memory, in the same regions where neurons had died.

Blocking arginase using the small drug difluoromethylornithine (DFMO) before the start of symptoms in the mice, the scientists saw fewer CD11c microglia and plaques develop in their brains. These mice performed better on memory tests.

“All of this suggests to us that if you can block this local process of amino acid deprivation, then you can protect — the mouse, at least — from Alzheimer’s disease,” Kan said.

Duke University

DFMO is being investigated in human clinical trials to treat some types of cancer, but it hasn’t been tested as a potential therapy for Alzheimer’s. In the new study, Colton’s group administered it before the onset of symptoms; now they are investigating whether DFMO can treat features of Alzheimer’s after they appear.

Does the study suggest that people should eat more arginine or take dietary supplements? The answer is ‘no,’ Colton said, partly because a dense mesh of cells and blood vessels called the blood-brain barrier determines how much arginine will enter the brain. Eating more arginine may not help more get into the sites of the brain that need it. Besides, if the scientists’ theory is correct, then the enzyme arginase, unless it’s blocked, would still break down the arginine.

“We see this study opening the doors to thinking about Alzheimer’s in a completely different way, to break the stalemate of ideas in AD,” Colton said. “The field has been driven by amyloid for the past 15, 20 years and we have to look at other things because we still do not understand the mechanism of disease or how to develop effective therapeutics.”

- MFP News Services
- 5/12/2015