New immune therapy successfully treats brain tumors in mice

Using an artificial protein that stimulates the body’s natural immune system to fight cancer, a research team at Duke Medicine has engineered a lethal weapon that kills brain tumors in mice while sparing other tissue. If it can be shown to work in humans, it would overcome a major obstacle that has hampered the effectiveness of immune-based therapies.

The protein is manufactured with two arms – one that exclusively binds to tumor cells and another that snags the body’s fighter T-cells, spurring an attack on the tumor. In six out of eight mice with brain tumors, the treatment resulted in cures, according to findings published Dec. 17, 2012, in the Proceedings of the National Academy of Sciences.

"This work represents a revival of a somewhat old concept that targeting cancer with tumor-specific antigens may well be the most effective way to treat cancer without toxicity," said senior author John H. Sampson, M.D., PhD, a neurosurgeon at The Preston Robert Tisch Brain Tumor Center at Duke. "But there have been problems with that approach, especially for brain tumors. Our therapeutic agent is exciting, because it acts like Velcro to bind T-cells to tumor cells and induces them to kill without any negative effects on surrounding normal tissues."

Sampson and colleagues focused on the immune approach in brain tumors, which are notoriously difficult to treat. Despite surgery, radiation and chemotherapy, glioblastomas are universally fatal, with a median survival of 15 months.

Immunotherapies, in which the body’s B-cells and T-cells are triggered to attack tumors, have shown promise in treating brain and other cancers, but have been problematic in clinical use. Treatments have been difficult to administer at therapeutic doses, or have spurred side effects in which the immune system also attacks healthy tissue and organs.

Working to overcome those pitfalls, the Duke-led researchers designed a kind of connector - an artificial protein called a bispecific T-cell engager, or BiTE – that tethers the tumor to its killer. Their newly engineered protein includes fractions of two separate antibodies, one that recruits and engages the body’s fighter T-cells and one that expressly homes in on an antigen known as EGFRvIII, which only occurs in cancers.

Once connected via the new bispecific antibody, the T-cells recognize the tumor as an invader, and mount an attack. Normal tissue, which does not carry the tumor antigen, is left unscathed.

European Project Aims To Create 1,500 New Stem Cell Lines

A joint public-private collaboration between the European Union and Europe’s pharmaceutical industry, called the StemBANCC project, will spend nearly 50 million euros to create 1,500 pluripotent stem cell lines. But the initiative’s goal isn’t to find a stem cell-based cure for diabetes or Alzheimer’s disease. They hope instead that their stem cell lines will prove to be faster and more effective drug screens in the search for drugs to fight these and other conditions.

A frustrating problem in medical research is the inadequacy of animal models. All too often a treatment works great in laboratory rats or mice but then its efficacy fails to repeat in human trials. But researchers are beginning to capitalize on the potential of stem cells – not as cures, but as means to finding cures.

Scientists are becoming more adept at turning skin cells into pluripotent stem cells, which can then be converted to other cell types such as neurons or heart cells. And because these are human cells they are superior to animal models for drug screening or toxicity testing. Human cell lines have been used for many years, but before pluripotent stem cells creating cell lines involved immortalizing the cells and thus drastically changing their physiology.

The goal of StemBANCC is to use these human-induced pluripotent stem cells as a drug discovery platform to treat the following 8 common diseases: Alzheimer’s disease, Parkinson’s disease, autism, schizophrenia, bipolar disorder, migraine, pain and diabetes. Studying these conditions typically involves creating an animal model, such as a rat that exhibits some behavioral hallmarks of autism after being given valproic acid. The cells from StemBANCC would improve upon animal models by providing, not only cells from humans but cells from patients with the actual disorders being studied. Skin cells gotten from a schizophrenia patient and converted (via pluripotency) to neurons, for instance, would give scientists a powerful tool with which to screen drugs.

Led by Oxford University, StemBANCC will involve 10 pharmaceutical companies and 23 academic institutions across 11 different countries. Part of the Innovative Medicines Initiative that pairs the European Union and the pharmaceutical industry. The EU is contributing 26 million euros ($33.5 million). Another 21 million euros ($27 million) are coming from the pharmaceutical industry. StemBANCC’s “kick-off” meeting took place in 2012 in Basel, Switzerland.

Zameel Cader, neurologist at the University of Oxford and a leader on the project, told Nature, “We’re specifically trying to develop a panel of lines across a range of diseases that are important to address. There isn’t another institution that’s doing this at the same scale across the same range of diseases.”

The hype surrounding stem cells typically extolls their virtues as a miraculous ‘cure all’ replacing damaged or diseased cells with new, healthy ones. And while stem cells have given blind people back part of their sight and have shown to restore some hearing in animals or even help paralyzed ones walk again in the lab, mainstream cures derived from stem cells are still rare. In the meantime, places like StemBANCC can pursue the less sexy, perhaps, but more reachable near term benefits of stem cells.

Study paves way to design drugs aimed at multiple protein targets at once

An international research collaboration led by scientists at the University of North Carolina School of Medicine and the University of Dundee, in the U.K., have developed a way to efficiently and effectively make designer drugs that hit multiple protein targets at once.

This accomplishment, described in the Dec. 13, 2012 issue of the journal Nature, may prove invaluable for developing drugs to treat many common human diseases such as diabetes, high blood pressure, obesity, cancer, schizophrenia, and bi-polar disorder.

These disorders are called complex diseases because each have a number of genetic and non-genetic influences that determine susceptibility, i.e., whether someone will get the disease or not.

“In terms of the genetics of schizophrenia we know there are likely hundreds of different genes that can influence the risk for disease and, because of that, there’s likely no single gene and no one drug target that will be useful for treating it, like other common complex diseases,” said study co-leader, Brian L. Roth, MD, PhD, Michael J. Hooker Distinguished Professor of Pharmacology in the UNC School of Medicine, professor in the Division of Chemical Biology and Medicinal Chemistry in the UNC Eshelman School of Pharmacy, and director of the National Institute of Mental Health Psychoactive Drug Screening Program.

In complex neuropsychiatric conditions, infectious diseases and cancer, Roth points out that for the past 20 years drug design has been selectively aimed at a single molecular target, but because these are complex diseases, the drugs are often ineffective and thus many never reach the market.

Moreover, a drug that acts on a single targeted protein may interact with many other proteins. These undesired interactions frequently cause toxicity and adverse effects. “And so the realization has been that perhaps one way forward is to make drugs that hit collections of drug targets simultaneously. This paper provides a way to do that,” Roth said.

The new way involves automated drug design by computer that takes advantage of large databases of drug-target interactions. The latter have been made public through Roth’s lab at UNC and through other resources.

Another Muscular Dystrophy Mystery Solved; MU Scientists Inch Closer to a Therapy for Patients

Approximately 250,000 people in the United States suffer from muscular dystrophy, which occurs when damaged muscle tissue is replaced with fibrous, bony or fatty tissue and loses function. Three years ago, University of Missouri scientists found a molecular compound that is vital to curing the disease, but they didn’t know how to make the compound bind to the muscle cells. In a new study, published in the Proceedings of the National Academies of Science, MU School of Medicine scientists Yi Lai and Dongsheng Duan have discovered the missing pieces to this puzzle that could ultimately lead to a therapy and, potentially, a longer lifespan for patients suffering from the disease.

Duchenne muscular dystrophy (DMD), predominantly affecting males, is the most common type of muscular dystrophy. Patients with Duchenne muscular dystrophy have a gene mutation that disrupts the production of dystrophin, a protein essential for muscle cell survival and function. Absence of dystrophin starts a chain reaction that eventually leads to muscle cell degeneration and death. While dystrophin is vital for muscle development, the protein also needs several “helpers” to maintain the muscle tissue. One of these “helper” molecular compounds is nNOS, which produces nitric oxide that can keep muscle cells healthy after exercise.

“Dystrophin not only helps build muscle cells, it’s also a key factor to attracting nNOS to the muscles cells and helping nNOS bind to the cell and help repair it following activity,” said Lai, a research assistant professor in the Department of Molecular Microbiology and Immunology. “Prior to this discovery, we didn’t know how dystrophin made nNOS bind to the cells. What we found was that dystrophin has a special ‘claw’ that is used to grab nNOS and bring it close to the muscle cell. Now that we have that key, we hope to begin the process of developing a therapy for patients.”

Listen up, doc: Empathy raises patients’ pain tolerance

A doctor-patient relationship built on trust and empathy doesn’t just put patients at ease – it actually changes the brain’s response to stress and increases pain tolerance, according to new findings from a Michigan State University research team.

Medical researchers have shown in recent studies that doctors who listen carefully have happier patients with better health outcomes, but the underlying mechanism was unknown, said Issidoros Sarinopoulos, professor of radiology at MSU.

“This is the first study that has looked at the patient-centered relationship from a neurobiological point of view,” said Sarinopoulos, the lead researcher. “It’s important for doctors and others who advocate this type of relationship with the patient to show that there is a biological basis.”

Published in the journal Patient Education and Counseling, the study was part of a broader effort at MSU, led by professor of medicine Robert Smith, to establish standards for patient-centered health care and measure its effectiveness.

“Medicine has for too long focused just on the physical dimensions of the patient,” said Smith, who co-authored the paper. “Those clinical questions are important and necessary, but we’re trying to demonstrate that when you let patients tell their story in an unfettered way, you get more satisfied patients who end up healthier.”

An antidote for hypersomnia

Researchers at Emory University School of Medicine have discovered that dozens of adults with an elevated need for sleep have a substance in their cerebrospinal fluid that acts like a sleeping pill.

The results are scheduled for publication online Wednesday by the journal Science Translational Medicine.

Some members of this patient population appear to have a distinct, disabling sleep disorder called “primary hypersomnia,” which is separate from better-known conditions such as sleep apnea or narcolepsy. They regularly sleep more than 70 hours per week and have difficulties awakening. When awake, they still have reaction times comparable to someone who has been awake all night. Their sleepiness often interferes with work or school attendance, and conventional treatments such as stimulants bring little relief.

"These individuals report feeling as if they’re walking around in a fog — physically, but not mentally awake," says lead author David Rye, professor of neurology at Emory University School of Medicine and director of research for Emory Healthcare’s Program in Sleep. "When encountering excessive sleepiness in a patient, we typically think it’s caused by an impairment in the brain’s wake systems and treat it with stimulant medications. However, in these patients, the situation is more akin to attempting to drive a car with the parking brake engaged. Our thinking needs to shift from pushing the accelerator harder, to releasing the brake."

In a clinical study with seven patients who remained sleepy despite above-ordinary sleep amounts and treatment with stimulants, Emory researchers showed that treatment with the drug flumazenil can restore alertness, although flumazenil’s effectiveness was not uniform for all seven. Alertness was gauged through the psychomotor vigilance test, a measurement of reaction time.

Breakthrough nanoparticle halts multiple sclerosis

In a breakthrough for nanotechnology and multiple sclerosis, a biodegradable nanoparticle turns out to be the perfect vehicle to stealthily deliver an antigen that tricks the immune system into stopping its attack on myelin and halt a model of relapsing remitting multiple sclerosis (MS) in mice, according to new Northwestern Medicine research.

The new nanotechnology also can be applied to a variety of immune-mediated diseases including Type 1 diabetes, food allergies and airway allergies such as asthma.

In MS, the immune system attacks the myelin membrane that insulates nerves cells in the brain, spinal cord and optic nerve. When the insulation is destroyed, electrical signals can’t be effectively conducted, resulting in symptoms that range from mild limb numbness to paralysis or blindness. About 80 percent of MS patients are diagnosed with the relapsing remitting form of the disease.

The Northwestern nanotechnology does not suppress the entire immune system as do current therapies for MS, which make patients more susceptible to everyday infections and higher rates of cancer. Rather, when the nanoparticles are attached to myelin antigens and injected into the mice, the immune system is reset to normal. The immune system stops recognizing myelin as an alien invader and halts its attack on it.

"This is a highly significant breakthrough in translational immunotherapy," said Stephen Miller, a corresponding author of the study and the Judy Gugenheim Research Professor of Microbiology-Immunology at Northwestern University Feinberg School of Medicine. "The beauty of this new technology is it can be used in many immune-related diseases. We simply change the antigen that’s delivered."

"The holy grail is to develop a therapy that is specific to the pathological immune response, in this case the body attacking myelin," Miller added. "Our approach resets the immune system so it no longer attacks myelin but leaves the function of the normal immune system intact."

The nanoparticle, made from an easily produced and already FDA-approved substance, was developed by Lonnie Shea, professor of chemical and biological engineering at Northwestern’s McCormick School of Engineering and Applied Science.

"This is a major breakthrough in nanotechnology, showing you can use it to regulate the immune system," said Shea, also a corresponding author. The paper was published Nov. 18 in the journal Nature Biotechnology.

Medical vital-sign monitoring reduced to the size of a postage stamp

Electrical engineers at Oregon State University have developed new technology to monitor medical vital signs, with sophisticated sensors so small and cheap they could fit onto a bandage, be manufactured in high volumes and cost less than a quarter.

A patent is being processed for the monitoring system and it’s now ready for clinical trials, researchers say. When commercialized, it could be used as a disposable electronic sensor, with many potential applications due to its powerful performance, small size, and low cost.

Heart monitoring is one obvious candidate, since the system could gather data on some components of an EKG, such as pulse rate and atrial fibrillation. Its ability to measure EEG brain signals could find use in nursing care for patients with dementia, and recordings of physical activity could improve weight loss programs. Measurements of perspiration and temperature could provide data on infection or disease onset.

And of course, if you can measure pulse rate and skin responses, why not a lie detector?

“Current technology allows you to measure these body signals using bulky, power-consuming, costly instruments,” said Patrick Chiang, an associate professor in the OSU School of Electrical Engineering and Computer Science.

“What we’ve enabled is the integration of these large components onto a single microchip, achieving significant improvements in power consumption,” Chiang said. “We can now make important biomedical measurements more portable, routine, convenient and affordable than ever before.”

The much higher cost and larger size of conventional body data monitoring precludes many possible uses, Chiang said. Compared to other technologies, the new system-on-a-chip cuts the size, weight, power consumption and cost by about 10 times.

Biocompatible sponge can be injected to deliver stem cells and drugs into the body

Biocompatible scaffolds, like those developed to stimulate the repair of heart tissue and bone and cartilage in the body, would normally need to be implanted surgically. Now bioengineers at Harvard University have developed a compressible bioscaffold that can be delivered via a syringe before popping back to its original shape inside the body. The material is also able to be loaded up with drugs or living cells that are gradually released as the material breaks down.

The injectable sponge is made up primarily of a seaweed-based jelly called alginate. It is actually a sponge-like gel that is formed through a freezing process called cryogelation. When the water in the alginate solution starts to freeze, pure ice crystals are formed and the surrounding gel becomes more concentrated as it sets. Later, the ice crystal melt to leave a network of large pores that allow liquids and large molecules to easily flow through it. Live cells can be attached to the walls of this network and large and small proteins and drugs can also be held within the alginate jelly itself.

Unlike other alginate gels that are brittle, using this method the researchers were able to produce a strong, compressible gel by carefully calibrating the alginate mixture and the timing of the freezing process.

The research team led by principal investigator David J. Mooney, the Robert P. Pinkas Family Professor of Bioengineering at the Harvard School of Engineering and Applied Sciences (SEAS), demonstrated that cells and drugs can be delivered into the body intact along with the sponge through a small bore needle. Once inside the body, the sponge returns to its original shape and gradually releases its cargo as it breaks down.

“What we’ve created is a three-dimensional structure that you could use to influence the cells in the tissue surrounding it and perhaps promote tissue formation,” explains Mooney. “The simplest application is when you want bulking. If you want to introduce some material into the body to replace tissue that’s been lost or that is deficient, this would be ideal. In other situations, you could use it to transplant stem cells if you’re trying to promote tissue regeneration, or you might want to transplant immune cells, if you’re looking at immunotherapy.”