New treatment for Adenovirus

An investigational smallpox drug may also protect against adenovirus, which causes upper respiratory infections and some cases of the common cold. The key to getting a drug into clinical (human) trials is first having reliable animal studies that demonstrate its effectiveness. With that data, the FDA can design human trials to test it.

Currently, there are no drugs specifically approved to treat adenovirus because there have been no animal models to test their effectiveness. Saint Louis University researchers have solved that problem by realizing that the Syrian golden hamster is a good animal model here. “Adenoviruses tend to be species-specific; however, we found that the human adenovirus will replicate fairly well in the Syrian hamster, and if we depress its immune system, the virus will replicate very well. Once we understood that, we could test drugs that inhibit replication,” explains Dr. William Wold, chair of molecular microbiology and immunology at Saint Louis University School of Medicine and the lead author on the study results.

The drug, CMX001, is made by Chimerix and has been in development to protect against smallpox and monkeypox, and as an antiviral agent in transplant patients. SLU researchers found, however, that CMX001 also protected the hamsters against the adenovirus by greatly reducing the ability of the virus to replicate in key organs, especially the liver. “CMX001 has a lipid (fat) group attached to the molecule, allowing the drug to pass through cell membranes to get at the virus replicating inside the cell,” says Wold. “It’s because of this membrane permeability that the drug can be administered orally. It is absorbed through cells lining the intestine into the bloodstream, where it is carried to other cells. We can use low doses without harming the kidneys.”

There are about 50 serotypes of adenoviruses. The strain being tested is associated with upper respiratory infections in children and some common colds. Adenoviruses can be very serious in immunosuppressed patients, like those with organ transplants. Armed with the hamster trial data, Chimerix is in the process of developing a clinical trial of CMX001 against a number of viruses. Wold’s data will help them gain FDA approval.

“This is very exciting because people die of respiratory disease,” he says. “One very severe serotype of adenovirus causes acute respiratory disease, which tends to develop in military boot camps where recruits are under a great deal of stress and living in close quarters.”

Parkinson’s root Found

Researchers at Saint Louis University have identified the key brain chemical that causes the symptoms of Parkinson’s disease, something that affects 1.5 million Americans. That identification paves the way for drug therapies to prevent the disease. Parkinson’s occurs when neurons, or nerve cells, in a specific part of the brain start to die. These neurons produce dopamine, the chemical responsible for smooth, coordinated function of the body’s muscles and movements. When about 80 percent of these dopamine neurons die or are damaged, symptoms of Parkinson’s start to appear: tremors and shaking, slowness of movement, rigidity and stiffness, halting speech, and difficulty with balance.

Current therapies for Parkinson’s involve replacing lost dopamine when the cells that produce it die off. This new discovery helps scientists work toward neuroprotective therapies to prevent the cell deaths in the first place. William J. Burke, M.D., Ph.D., is a professor of neurology at Saint Louis University and the lead author of this study. “The main functioning part of the brain consists of 200 billion neurons. Of these, 400,000 are dopamine neurons,” he notes. “They release dopamine as a neurotransmitter to allow these neurons to communicate and keep us functioning. In Parkinson’s disease, these neurons die. Why these and not the others?”

Scientists have long known that a key protein called alpha-synuclein contributes to neuron cell death when it clumps together. What they didn’t know is why this protein clumps in these patients. This latest study shows that in the process that leads to Parkinson’s disease, dopamine is converted into a highly toxic chemical called DOPAL, which then causes the alpha-synuclein protein to clump. “It’s actually DOPAL that kicks this whole process off and results in Parkinson’s. We also know that an enzyme, monaminoxidase (MAO), causes the dopamine to break down into DOPAL. Logically, we want to inhibit this enzyme from doing that, and there are already monaminoxidase inhibitors on the market.”

With this latest information, Burke and his colleagues have set up additional animal studies to test the effects of MAO inhibitors on DOPAL formation. “Our goal, now that we know DOPAL is the primary cause of Parkinson’s disease, is to look for therapies to block its toxic effects, block its formation, and break it down into non-toxic byproducts. We now have several ways to approach this.”

Questioning Ultrasound Agents

A warning the FDA recently placed on a diagnostic tool could prevent physicians from detecting life-threatening cardiac events, says a Saint Louis University cardiologist. In October 2007, the FDA placed a black-box warning on ultrasound contrast agents used to improve the quality of echocardiography images in patients who might otherwise not have optimal images. A black-box warning is given to drugs that carry a significant risk of serious or even life-threatening adverse effects. This particular warning was issued without a formal examination of the risks and benefits of using them, says Dr. Melda Dolan, associate professor of cardiology, Saint Louis University School of Medicine.

Echocardiography is an important diagnostic tool in determining left ventricular function. For diagnosing hard-to-identify conditions such as hypertrophic cardiomyopathy (HCM), a condition that affects young athletes and can result in sudden death, it is the gold standard. “It can be very difficult to make a diagnosis without contrast,” Dolan notes. “We have to be able to see specific segments in atrial-ventricular function. In a stress echocardiogram, it’s even more important to see clearly because diagnosis is based on abnormal wall motion. At least 30 percent of patients have suboptimal studies because without contrast, we lose the border definition when the heart rate increases.”

Based on the results of this study, the FDA should reconsider its stance on contrast agents because the benefits outweigh the potential, says Dolan, primary investigator of the study. To evaluate the overall risk and benefits of ultrasound contrast agents, researchers from initially the Saint Louis University and University of Nebraska hospitals, and later Mayo Clinic, looked at almost 40,000 patients who received contrast agents during an echocardiogram and compared their experience with those of a group of more than 6,000 patients who did not receive the agents. They looked at short-term (30 minutes after infusion) and long-term (within 24 hours) outcomes and noted any adverse events or deaths. There were no adverse events that could be attributed to the contrast agents. “Our research indicates that contrast agents can safely be used in patients to provide optimal imaging,” Dolan concludes.

Slowing Alzheimer’s

Researchers have discovered that in mice, increasing levels of a protein that helps the brain use cholesterol may slow the development of Alzheimer’s disease. A new study published in January gives new possibilities for effective treatment and even prevention of the plaque build-up characteristic of the disease. Dr. David Holtzman is senior author of the study and chair of the department of neurology at Washington University School of Medicine. His excitement about these findings is based on this new approach of helping the brain use fats to prevent the protein malformation that creates plaque. The study protein, ABCA1, is looking promising as a good drug target for Alzheimer’s therapies.

“There are known drugs that can increase ABCA1 levels, and with some further development of this or similar classes of drugs, and additional insights into how ABCA1 slows down plaque deposition, there may be a way to create a new approach to Alzheimer’s treatment,” he says. Discovered in 2001, ABCA1 is a naturally occurring enzyme already under study for its potential to treat heart disease. Lipids like cholesterol aren’t soluble, so to be transported through the bloodstream and into and out of cells, they have to hook up with molecules known as apolipoproteins, whose function is to facilitate the solubility process called lipidation. In the bloodstream, ABCA1 lipidates HDL with cholesterol to form fully functioning HDL, the good cholesterol believed to reduce heart disease risk. Drugs are now in clinical testing that increase ABCA1 levels with the hope of preventing or curing atherosclerosis.

Holtzman focused on the connection between ABCA1 and lipidation because a primary risk factor for Alzheimer’s disease is an apolipoprotein called apoE. The thrust of the current study suggests that ABCA1 facilitates lipidation of apoE, allowing it to better scavenge amyloid beta, the main ingredient in plaque. Mice created to have high levels of ABCA1 in their brains, when crossbred with mice bred to have Alzheimer’s disease, produced mice with high ABCA1 brain levels and less plaque development than those with normal ABCA1 levels.

Drugs that increase the amount of ABCA1, called LXR agonists, are in development. LXR agonists are still in the animal study phase, but Holtzman believes they are close to getting good drugs into human studies. Additional work is underway in Holtzman’s laboratory to further clarify the relationship between ABCA1, apoE and amyloid beta.

Oral MS Medication

Currently, there are no oral medications approved to treat multiple sclerosis (MS), which affects about 400,000 people in the U.S. and results in 10,000 new diagnoses each year. About 85 percent of patients with MS have a form called relapsing-remitting MS, characterized by periodic attacks or flare-ups (relapses), followed by months or years of little sign of remission. The different medications in use to slow or modify the progression of the disease must all be injected into the skin, muscle or veins. These FDA-approved drugs have effected about a 30 percent decrease in relapse.

Saint Louis University is one of several dozen sites around the world that will take part in a study testing how patients with relapsing-remitting MS respond to an experimental oral medication called laquinimod, which is taken as a tablet once a day. “Laquinimod seems to modulate how the immune system works,” says Florian Thomas, M.D., Ph.D., professor of neurology and psychiatry at Saint Louis University School of Medicine and the site’s principal investigator. He also directs the National MS Society-certified MS Centers at both Saint Louis University and the VA Hospital. “In smaller earlier trials, the drug reduced the likelihood of relapses in patients, as well as the number of MS lesions seen on MRI scans.”

In the new double-blind study, half the projected 1,000 volunteer patients will receive laquinimod, while the other half will be given a placebo. The randomized trial will last for 30 months, during which time researchers will periodically assess how the disease progresses. At various visits, patients will be given physical and neurological exams and an MRI scan to determine the extent of scarring on the brain. Anyone in the study who experiences a flare-up will be treated according to conventional medical protocols.

As Thomas explains: “The way the drug works is by changing the immune response from inflammatory to anti-inflammatory. It does not act as an immune suppressant, which is important for maintaining the safety of the drug. The goal is to prevent myelin and nerve damage. If myelin, the sheath around the nerve, is damaged, it can regenerate, which leads to remission. If the nerve fiber itself is damaged, that’s more serious.” He says there is a great need for an oral agent to treat MS because some people don’t tolerate injections or are adverse to them. For more information about participation in the laquinimod study, call 977-4900.

Heart Disease & Kidneys

For the 19 million Americans living with chronic kidney disease (CKD), a real danger is death from cardiovascular disease due to the high levels of blood phosphate the kidneys aren’t regulating. This link was only recently identified by researchers at Washington University School of Medicine. They were able to demonstrate that high blood phosphate directly stimulates calcification of blood vessels and that phosphate-binding drugs can decrease this process.

“One of the kidney’s functions is to help maintain a constant balance of phosphate in the bloodstream,” says senior author Dr. Keith Hruska, director of pediatric nephrology. “When kidney failure occurs, an excess of serum phosphate develops. We found that high phosphate serves as a signal that stimulates cells within blood vessel walls to deposit calcium crystals. That produces vascular stiffness, a cause of cardiovascular mortality.”

Currently, phosphate-binding drugs are on the market and approved by the FDA for patients on dialysis. The drug companies have provided the FDA with the background to demonstrate the need to extend that drug to patients with CKD before dialysis is necessary. “We anticipate that approval anytime,” says Hruska. “When it comes through, physicians will be able to treat CKD patients on-label with these drugs. That treatment will be covered by insurance, and it will provide an impetus for physicians to more aggressively treat high serum phosphate.”

Hruska says large-scale population studies have demonstrated that serum phosphate levels may be as important as serum cholesterol levels in predicting cardiovascular problems. The mechanism they observed in the study, which causes the skeleton to be unable to absorb excess phosphates, is also present in elderly people with osteoporosis. Diabetes, which is on the rise, can also lead to kidney damage and high serum phosphate, so those with the disease can also benefit from phosphate-binding drugs.

“Once we prove that managing serum phosphate levels results in better long-term clinical outcomes, perhaps we can get primary care doctors to be aware of this and make sure those issues are managed,” Hruska concludes.

Viral Infections & Asthma

Babies who contract severe viral respiratory infections may have a higher rate of asthma as they get older. Researchers at Washington University School of Medicine have identified several key steps in the development of asthma in mice after viral infections. In the U.S., the number of people with asthma rose from 7 million in 1980 to about 20 million in 2003. Research suggests that growing population density and the resulting increase in transmission of respiratory viral infections may be a cause.

Several studies back this up. Fewer than one in 30 people who don’t have a severe respiratory infection in infancy develop asthma, but of those who get an infection, the rate is one in five. Researchers theorize that in genetically predisposed individuals, this kind of immune reaction to an infection can occur. In one study published in 2007, researchers discovered that during the infection, the mice produced antibodies and immune system signals similar to those produced during an allergic response, instead of those normally made in response to infection. That started a chain reaction leading to asthma. Researchers believe that a similar reaction occurs in some people in response to severe viral infections.

Dr. Michael Holtzman, director of pulmonary and critical care medicine at Washington University School of Medicine, explains, “The virus infects the dendritic cell and stimulates its IgE receptors. Those in turn stimulate T-cells, which leads to interleukin 13 (IL-13) production known to turn lung airway cells into mucous cells that clog the airways and cause the shortness of breath characteristic of asthma. We want to know how we can interfere with the process and alter this abnormal immune response. We need to remove the inflammatory compounds, and there are several points in the process where this can happen.” Researchers indeed found that interfering with this process prevented overgrowth of mucous-producing cells.

“In mice, at whichever step in the process we intervene, everything is blocked downstream,” Holtzman notes. He says the therapeutic targets include blocking T-cell activation with a compound called CCL28, a monoclonal antibody administered as an inhalant. “Another clinical approach is a vaccine against the virus. If we understand how the virus does what it does, we can develop something to head it off.”

Tantrums in Preschoolers

According to Washington University researchers, certain types of tantrums in preschoolers may be signs of emotional or behavioral problems that should be treated. While temper tantrums are normal in young children, long, frequent, violent and/or self-destructive outbursts may not be. Researchers compared tantrums in healthy children to the tantrums in children diagnosed with depression or disruptive disorders, and healthy children were found to be less aggressive and have shorter tantrums than their peers with psychiatric disorders.

First author Andrew Belden, Ph.D., of Washington University School of Medicine says, “Healthy children may display extreme behaviors if they are tired, sick or hungry. But if a child is regularly engaging in specific types of tantrum behaviors, there may be a problem.” The study, which followed 3- to 6-year-olds over several years, identified five tantrum behaviors that appeared to be connected with depression or diagnosable disruptive disorders.

The first is extremely aggressive behavior during a tantrum. When a toddler displays aggression directly at a caregiver or is violently destructive during tantrums, parents should be concerned. The second behavior is intentional self-injury, such as scratching until the skin bleeds, head banging or self-biting. Other red flags include more than five tantrums a day for several days, very long tantrums, or inability to calm themselves following a tantrum.

Belden became interested in tantrum behaviors after watching the different styles of his own two children. He urges parents not to worry when a child has a tantrum, but to pay attention during these episodes. “We wanted to identify red flags for parents and health care providers,” he says. “These behaviors are not tied directly to a specific diagnosis.”

In some cases, Belden adds, parent-child dynamics may be precipitating these behaviors and parents may need help changing trigger behaviors. “We’re now looking at what moderates these tantrums and how parents can influence them. It could be as simple as a bad habit that needs to be changed.”

Genetics and Breast Tumors

Some breast cancer tumors that appear to be low-risk for recurrence are actually wolves in sheep’s clothing, according to researchers at Washington University School of Medicine. “We’ve been interested in how to predict relapse in patients with estrogen receptor-positive breast cancer,” says Matthew Ellis, M.D., Ph.D., an oncologist at Siteman Cancer Center. “Estrogen-positive tumors should respond well to hormone suppressant therapy, but not all of them do. With this new protocol for genetic profiles, we can identify the tumors that don’t and treat those patients more aggressively.”

Until now, doctors had no way to know some tumors would be unresponsive to therapy because their pathology was deceptive: The tumors appeared to be the more easily treatable estrogen receptor-positive tumors, but they rapidly lost their estrogen receptors. The chance for cancer recurrence in such patients is significantly higher, and standard post-operative care with long-term anti-estrogen therapy is often not effective. “When these patients come in, their tumors test positive for estrogen receptors, so they are started on anti-estrogen treatment with the belief that they will do fine,” Ellis explains. “But these tumors don’t depend on estrogen at all for growth and will keep growing during the therapy.”

The testing involves a genetic profile of a tumor biopsy sample at diagnosis, using a 50-gene signature. Then one month after letrozole therapy, an aromatase inhibitor that suppresses estrogen production, a second biopsy and genetic profile is run. In the low-risk group during the first study, 81 percent of patients showed a complete or partial response to treatment. Those patients then had surgery, followed by letrozole and radiation or chemotherapy. In the medium-risk group, 70 percent had a favorable response to the initial letrozole. The high-risk group had only a 25 percent response rate. A clinical test for the high-risk gene expression signature is expected to be available later this year and will be validated in clinical trials.

Ellis says it should be easy to incorporate the test into standard breast cancer therapy protocols. As soon as patients are diagnosed with estrogen receptor-positive cancer, they would be placed on an anti-estrogen agent like letrozole.

“Our goal is to identify the estrogen-positive but hormone unresponsive tumors in a more reliable way, to treat these patients more aggressively with chemotherapy, and continue to find more effective therapies as we further dissect what makes these tumors tick.”