New gene therapy shows broad protection in animal models to pandemic flu strains
Researchers at the Perelman School of Medicine, University of Pennsylvania have developed a new gene therapy to thwart a potential influenza pandemic. Specifically, investigators in the Gene Therapy Program, Department of Pathology and Laboratory Medicine, directed by James M. Wilson, MD, PhD, demonstrated that a single dose of an adeno-associated virus (AAV) expressing a broadly neutralizing flu antibody into the nasal passages of mice and ferrets gives them complete protection and substantial reductions in flu replication when exposed to lethal strains of H5N1 and H1N1 flu virus. These strains were isolated from samples associated from historic human pandemics – one from the infamous 1918 flu pandemic and another from 2009.
Wilson, Anna Tretiakova, PhD, Senior Research Scientist, Maria P. Limberis, PhD, Research Assistant Professor, all from the Penn Gene Therapy Program, and colleagues published their findings online in Science Translational Medicine ahead of print. In addition to the Penn scientists, the international effort included colleagues from the Public Health Agency of Canada, Winnipeg; the University of Manitoba, Winnipeg; and the University of Pittsburgh. Tretiakova is also the director of translational research, and Limberis is the director of animal models core, both with the Gene Therapy Program.
“The experiments described in our paper provide critical proofof- concept in animals about a technology platform that can be deployed in the setting of virtually any pandemic or biological attack for which a neutralizing antibody exists or can be easily isolated,” says Wilson. “Further development of this approach for pandemic flu has taken on more urgency in light of the spreading infection in China of the lethal bird strain of H7N9 virus in humans.”
Influenza infections are the seventh leading cause of death in the United States and result in almost 500,000 deaths worldwide per year, according to the US Centers for Disease Control. The emergence of a new influenza pandemic remains a threat that could result in a much loss of life and worldwide economic disruption.
Human antibodies with broad neutralizing activity against various influenza strains exist but their direct use as a prophylactic treatment is impractical. Now, yearly flu vaccines are made by growing the flu virus in eggs. The viral envelope proteins on the exterior, namely hemagglutinin, are cleaved off and used as the vaccine, but vary from year to year, depending on what flu strains are prevalent. However, high mutation rates in the proteins result in the emergence of new viral types each year, which elude neutralization by preexisting antibodies in the body.
This approach has led to annual vaccinations against seasonal strains of flu viruses that are predicted to emerge during the upcoming season. Strains that arise outside of the human population, for example in domestic livestock, are distinct from those that normally circulate in humans, and can lead to deadly pandemics.
These strains are also not effectively controlled by vaccines developed to human strains, as with the 2009 H1N1 pandemic. The vaccine development time for that strain, and in general, was not fast enough to support vaccination in response to an emerging pandemic.
Knowing this, the Penn team proposed a novel approach that does not require the elicitation of an immune response, which does not provide sufficient breadth to be useful against any strain of flu other than the one for which it was designed, as with conventional approaches.
The Penn approach is to clone into a vector a gene that encodes an antibody that is effective against many strains of flu and to engineer cells that line the nasal passages to express this broadly neutralizing antibody, effectively establishing broad-based efficacy against a wide range of flu strains.
Efficacy of the treatment was tested in mice that were exposed to lethal quantities of three strains of H5N1 and two strains of H1N1, all of which have been associated with historic human pandemics (including the infamous H1N1 1918).
Flu virus rapidly replicated in untreated animals all of which needed to be euthanized. However, pretreatment with the AAV9 vector virtually shut down virus replication and provided complete protection against all strains of flu in the treated animals. The efficacy of this approach was also demonstrated in ferrets, which provide a more authentic model of human pandemic flu infection.
“The novelty of this approach is that we’re using AAV and we’re delivering the prophylactic vaccine to the nose in a non-invasive manner, not a shot like conventional vaccines that passively transfer antibodies to the general circulation,” says Limberis.
“There’s a long history of using antibodies for cancer and autoimmune disease, but only two have been approved for infectious diseases,” notes Tretikova. “This novel technique has allowed for the development of a prophylactic passive vaccine that is cost effective, easily administered, and quickly manufactured.” The team is working with various stakeholders to accelerate the development of this product for pandemic flu and to explore the potential of AAV vectors as generic delivery vehicles for countermeasures of biological and chemical weapons.
Researchers discover molecule that triggers sensation of itch
Scientists at the US National Institutes of Health report they have discovered in mouse studies that a small molecule released in the spinal cord triggers a process that is later experienced in the brain as the sensation of itch.
The small molecule, called natriuretic polypeptide b (Nppb), streams ahead and selectively plugs into a specific nerve cell in the spinal cord, which sends the signal onward through the central nervous system. When Nppb or its nerve cell was removed, mice stopped scratching at a broad array of itch-inducing substances. The signal wasn’t going through.
Because the nervous systems of mice and humans are similar, the scientists say a comparable biocircuit for itch likely is present in people. If correct, this start switch would provide a natural place to look for unique molecules that can be targeted with drugs to turn off the sensation more efficiently in the millions of people with chronic itch conditions, such eczema and psoriasis.
The paper, published online May 24 in the journal Science, also helps to solve a lingering scientific issue. “Our work shows that itch, once thought to be a low-level form of pain, is a distinct sensation that is uniquely hardwired into the nervous system with the biochemical equivalent of its own dedicated land line to the brain,” said Mark Hoon, Ph.D., the senior author on the paper and a scientist at the National Institute of Dental and Craniofacial Research.
Hoon said his group’s findings began with searching for the signalling components on a class of nerve cells, or neurons, that contain a molecule called TRPV1. These neurons, with their long nerve fibres extending into the skin, muscle, and other tissues, help to monitor a range of external conditions, from extreme temperature changes to detecting pain.
Yet little is known about how these neurons recognize the various sensory inputs and, like sorting mail, know how to route them correctly to the appropriate pathway to the brain.
To fill in more of the details, Hoon said his laboratory identified in mice some of the main neurotransmitters that TRPV1 neurons produce.
The scientists screened the various neurotransmitters, including Nppb, to see which ones corresponded with transmitting sensation.
“We tested Nppb for its possible role in various sensations without success,” said Santosh Mishra, lead author on the study and a researcher in the Hoon laboratory. “When we exposed the Nppb-deficient mice to several itch-inducing substances, it was amazing to watch. Nothing happened. The mice wouldn’t scratch.”
Further experiments established that Nppb was essential to initiate the sensation of itch, known clinically as pruritus. Equally significant, the molecule was necessary to respond to a broad spectrum of pruritic substances. Previous research had suggested that a common start switch for itch would be unlikely, given the myriad proteins and cell types that seemed to be involved in processing the sensation.
Hoon and Mishra turned to the dorsal horn, a junction point in the spine where sensory signals from the body’s periphery are routed onward to the brain. Within this nexus of nerve connections, they looked for cells that expressed the receptor to receive the incoming Nppb molecules.
“The receptors were exactly in the right place in the dorsal horn,” said Hoon, the receptor being the long-recognized protein Npra. “We went further and removed the Npra neurons from the spinal cord. We wanted to see if their removal would shortcircuit the itch, and it did.”
Hoon said this experiment added another key piece of information. Removing the receptor neurons had no impact on other sensory sensations, such as temperature, pain, and touch. This told them that the connection forms a dedicated biocircuit to the brain that conveys the sensation of itch.
But the scientists had stepped into a conundrum. Previous reports had suggested that another neurotransmitter called GRP might initiate itch. If that wasn’t the case, where did GRP fit into the process?
They tested the receptor neurons that express GRP, finding the previous reports were correct about this molecule relaying the signal to the central nervous system. GRP just enters the picture after Nppb already has set the sensation in motion.
Mayo Clinic first to test stem cells in pediatric CHD patients
Mayo Clinic has announced the first U.S. stem cell clinical trial for pediatric congenital heart disease. The trial aims to determine how stem cells from autologous umbilical cord blood can help children with hypoplastic left heart syndrome (HLHS), a rare defect in which the left side of the heart is critically underdeveloped.
The trial will test the safety and feasibility of delivering a personalized cell-based therapy into the heart of 10 infants affected by HLHS. Today, treatment for babies born with HLHS involves three heart surgeries to redirect blood flow through the heart, or transplantation. The surgeries -- designed to provide adequate blood flow in and out of the heart, allowing the body to receive the oxygen-rich blood it needs – are typically performed over the first few years of life. For this study, stem cells from newborns with HLHS will be collected from the umbilical cord following birth. The cord blood will be sent to a Mayo Clinic lab for processing, where the stem cells will be separated from the other cells in the blood. The stem cells will then be frozen for preservation. During the baby’s second surgery for HLHS – typically performed at 4 to 6 months of age – the stem cells will be injected into the heart muscle.
“We want to see if these stem cells will increase the volume and strength of the heart muscle to give it greater durability and power to pump blood throughout the body,” says Harold Burkhart, M.D., a pediatric cardiovascular surgeon with the Mayo Clinic Children’s Center.
About 960 babies are born with hypoplastic left heart syndrome each year in the US, the Centers for Disease Control and Prevention estimates. In this syndrome, the left side of the heart can’t properly supply blood to the body because the lower left chamber (left ventricle) is too small or, in some cases, may not exist, Dr. Burkhart says. In addition, the valves on the left side of the heart (aortic valve and mitral valve) don’t work properly, and the main artery leaving the heart (aorta) is smaller than normal, he says.
“The care of these children with HLHS has been continuously improving since the first surgical procedure became available three decades ago, yet cardiac transplantation continues to be the limiting factor for far too many individuals,” says Timothy Nelson, M.D., Ph.D., director of the Todd and Karen Wanek Family Program for HLHS in Mayo Clinic’s Center for Regenerative Medicine. “Applying stem cellbased regeneration may offer a viable solution to help these children develop new tissues and grow stronger hearts.”
Qatar’s Sidra collaborates with US NIH to research new cancer therapies
A group of scientists including Sidra Medical and Research Center’s Chief Research Officer, Dr. Francesco M. Marincola, has discovered that a gene called Bach2 may play a central role in the development of a range of allergic and autoimmune diseases, such as multiple sclerosis, asthma, Crohn’s disease, celiac disease, and type-1 diabetes. The research has implications for the development of new therapies to target cancer. The findings were published in the prestigious journal Nature on June 2, 2013
The authors suggest that these findings may have implications for cancer treatment, since cancers use regulatory T cells to prevent their own destruction by antitumor immune responses. The team is now working toward manipulating the activity of the Bach2 gene with the goal of developing a new cancer immunotherapy. As this study was conducted in mice, it must be replicated in humans before its findings can be applied in a clinical setting.
“Sidra Medical and Research Center will continue along this line of research through direct collaboration with the US National Institutes of Health (NIH) to extend this observation toward its practical application to modulate the outcome of immune diseases by genetically regulating the function of Bach2 or other factors that regulate immune cell function,” said Marincola. “At Sidra we will carry out research to expand the scientific community’s understanding of a broad range of diseases that affect women and children around the world. I am delighted that we will be able to use our unique resources and expertise to expand this vital piece of research.”
Suicide risk factors mapped
A collaborative study between Lund University in Sweden and Stanford University in the US, showed that the rate of suicide among men is almost three times that of women. Being young, single and having a low level of education were stronger risk factors for suicide among men, while mental illness was a stronger risk factor among women. Unemployment was the strongest social risk factor among women, whereas being single was the strongest among men.
Because the study covered a range of different diseases in both in-patient and outpatient care as well as social factors, the researchers gained insight into which factors are particularly important to bear in mind when assessing the risk of suicide.
“Better strategies are needed for collaboration between different disciplines and wider society in order to reduce the risk of suicide for individuals who suffer from, for example, depression, anxiety, COPD, asthma and certain social risk factors,” says principal investigator Professor Jan Sundquist.
Of those who committed suicide, 29.5% of women and 21.7% of men had visited a doctor in the two weeks prior to their suicide, and 57.1% of women and 44.9% of men had visited a doctor within the 13 weeks prior to their suicide.
“This shows that many had contact with the health service a relatively short time before committing suicide. The results have clinical significance for those working in both primary care and other outpatient and in-patient care, including psychiatry. Besides the health service, social support services may need to be involved in the work to reduce the number of suicides in society,” says Sundquist. doi: 10.1017/S0033291713000810
Study shows Vit D supplement key for kids undergoing CHD surgery
Until now, there has been no research dedicated to the importance of Vitamin D supplementation in children with congenital heart disease (CHD). However, over the past few years, researchers at the Children’s Hospital of Eastern Ontario (CHEO) Research Institute and Cardiovascular Surgery Program teamed with the Canadian Critical Care Trials Group to understand the impact of cardiac surgery on the Vitamin D status of infants and children, due to be published in July in Anesthesiology.
“The importance of Vitamin D levels and supplementation in healthy infants and children is well established,” said Dr Dayre McNally, a clinical researcher and intensivist at CHEO and assistant professor in the Department of Pediatrics at the University of Ottawa. “Now we have more compelling evidence that children with congenital heart disease require even higher levels of Vitamin D intake in the months preceding surgery.”
This evidence comes from a study that looked at 58 children who had cardiac surgery at CHEO. Blood was collected at the time of admission to the Pediatric Intensive Care Unit immediately following surgery, and revealed that almost all of the children had low Vitamin D levels. With additional tests, the researchers were able to determine why. “Our results show that almost all children are Vitamin D deficient post-operatively as a result of borderline acceptable levels prior to surgery, combined with a 40% decline during the operation.”
The role of Vitamin D in the growth and maintenance of bone health is well known. However, recent studies have also suggested Vitamin D to be important for the proper functioning of other organs including the heart, lungs and immune systems. This study by Dr McNally confirms this, as patients with lower post-operative Vitamin D levels were more prone to requiring more lifesustaining therapies (medications to support heart function, longer duration of assisted breathing) and stayed in the Intensive Care Unit for longer periods of time.
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