While we go about our everyday lives, researchers at Saint Louis University and Washington University are busy solving some of the world’s most pressing health problems, moving from bench research to clinical trials to accepted practice.
[new respiratory therapies]
We need a cure for the common cold. An annoyance to most, a cold can be a harbinger of life-threatening lung disease for those with compromised immune systems. Also needed: drugs to effectively treat chronic obstructive pulmonary disease (COPD), cystic fibrosis and asthma, among others. Finding those takes money and hasn’t attracted the interest of deep-pocket pharmaceutical companies. Enter the National Institutes of Health. A Washington University drug discovery program has recently received $5 million in three new grants from the NIH to do just that.
The New Drug Discovery Program is housed in the Division of Pulmonary and Critical Care Medicine at Washington University School of Medicine, headed up by pulmonologist and principal investigator Dr. Michael Holtzman. “Chronic respiratory disease is the third-leading cause of death in the U.S. and fifth worldwide; these deaths are linked most strongly to overproduction of inflammatory mucus that blocks the airways,” he says.
Rather than go after the virus itself, this research is working on heightening the body’s ability to recognize and keep out a pathogenic virus, he explains. The problem with targeting a specific virus is that it mutates or we won’t get the right one, which is sometimes the problem with flu vaccines, he says. “Instead, we give a compound called a small molecule interferon signal enhancer, to tell the body to recognize a foreign virus and fight it.” One good candidate has already been identified for clinical trials. In the next few months, Holtzman’s group will seek FDA approval to test the safety of a new formulation of its antiviral compound for intranasal dosing.
[help for parents affected by autism]
Facing a new diagnosis of autism in your child can be devastating, and there haven’t been many resources to help parents manage it. Saint Louis University School of Medicine associate professor of pediatrics Debra Zand, Ph.D., is changing that. In a groundbreaking clinical trial, Zand and her team are running a program to help parents address and manage their children’s most challenging behaviors. The goal is to prevent the isolation for parents who avoid taking their child out in public for fear of a major meltdown.
Primary Care Stepping Stones – Positive Parenting Program, or PC-SS Triple P, is available at SSM Cardinal Glennon Children’s Medical Center. “We recruited 76 parents whose children, ages 2 to 12, were diagnosed as being on the autism spectrum this last year,” explains Zand. “We helped the parents identify and manage one or two of their most challenging behavior problems, behaviors that were causing stress in their lives and their marriages. We met with them once a week for four weeks to teach them new skills.”
They want to get parents at the beginning of the diagnosis, so the skills they learn can, over time, be transferred to other behaviors. Once parents have identified a problem, they can choose from a list of 25 evidence-based strategies to manage the behavior. Parents keep a behavior diary and behaviorists help them modify interventions that don’t work. By having concrete ways to deal with behavior issues, they can enjoy more normalcy and help their children function like other children. The parents report feeling empowered by this kind of support from professionals. Zand is applying for federal funding to expand the program throughout the city and to follow parents longer.
[pain ‘off’ switch]
Chronic neuropathic pain is a huge problem. Researchers at Saint Louis University School of Medicine have identified a nerve receptor that, then turned on, blocks pain signals. Daniela Salvemini, Ph.D., and her colleagues have discovered that by activating the A3 receptor in the brain and spinal cord with drugs called A3 agonists, they can prevent or reverse pain.
Says Salvemini, “The compound can be taken orally, but it would also work subcutaneously, spinally or topically. It showed a good effect across different types of pain in rodents, including chronic neuropathic pain caused by chemotherapy and bone cancer. This is exciting because we already knew that adenosine was effective. The problem was that it activates several receptors, some of which you don’t want to turn on because they create side effects. The adenosine 3 (A3) subtype seems to activate only the receptor we want, and it can be used in humans with a good safety profile.”
While controlling pain, it also can block withdrawal symptoms for people who have been taking opiates for their pain. She hopes to have the A3 agent in clinical trials within the next three years with chemotherapy-induced peripheral neuropathy as its main target, although it should also be effective for diabetic neuropathy pain.
Researchers hope to use these agonists to kills cancer cells and at the same time get rid of the dose-limiting toxicities of effective cancer treatments.
[hearing aids & balance]
We know that losing our hearing can lead to social isolation and a decreased quality of life, but research now indicates that uncorrected hearing also can lead to more falls. For people with osteoporosis and frailty, that’s not good. Dr. Timothy Hullar, an adjunct professor of otolaryngology at Washington University School of Medicine, reported on a small study that was the first to demonstrate that sound information, separate from the balance system in the inner ear, contributes to maintaining the body’s stability. The results were promising for improving hearing through aids or cochlear implants and for reducing the risk of falls in older people.
“I am continuing this research to see if the balance improvement is true for people with cochlear implants, and which groups it’s most useful for. For instance, is it better with two hearing aids than one? What the research implies is that hearing aids can be thought of also as balance aids, so if you have a relative who is resistant to having hearing corrected, that would be a good additional argument.”
In the study Hullar conducted at Washington University, he tested 14 people ages 65 to 91 with hearing aids in both ears. They performed significantly better on balance tests when their hearing aids were turned on. “We don’t think it’s just that wearing hearing aids makes a person more alert. The participants appeared to be using the sound information coming through their hearing aids as auditory reference points or landmarks to help maintain balance,” Hullar says.
[genes & smokers]
Two psychiatrist researchers at Washington University School of Medicine have identified a gene variant that is linked to people smoking longer and getting lung cancer sooner. By analyzing 24 studies of more than 29,000 smokers, Drs. Laura Bierut and Li-Shiun Chen have found that smokers with this variant are more likely to continue smoking four years longer and are diagnosed with lung cancer four years earlier than those without the variation in the CHRNA5 gene. It also appears to cause smokers to inhale more deeply, compounding the problem.
The good news is that those with the gene variant are more likely to respond to medications that help people quit smoking, such as Chantix and nicotine patches. So knowing the smoker’s genetic makeup could guide therapy. Chen, first author on the study, notes, “If we screen smokers routinely, we will get a lot of false positives for lung cancer. Spiral CT offer the best screening, but we should use it judiciously. Screening people before age 55 with that variant might make sense. Right now screening guidelines are by age. It would make more sense to use genotypes, the years of smoking and the amount they smoke to determine when we screen.”
Lung cancer has a five-year survival rate of 16 percent. Fifty percent of people diagnosed die within a year of diagnosis, so better screening criteria potentially can make a big difference.
[depressed? try laughing gas]
A pilot study at Washington University School of Medicine has shown early promise with nitrous oxide as a potential treatment for intractable depression. In 20 patients with treatment-resistant clinical depression, two-thirds showed an improvement in their symptoms after being given nitrous oxide, or laughing gas. Patients were evaluated the day of treatment and the next day.
Dr. Charles Conway, a psychiatrist, and his colleague, Dr. Charles Zorumski, joined forces with anesthesiologist Dr. Peter Nagele to try the therapy. “Other anesthetic agents, such as ketamine, seem to have an effect on depressive symptoms,” explains Nagele. “However, ketamine has drawbacks: it affects too many receptors; it can cause addiction; and it has side effects much like LSD, including memory loss. It also has to be given by IV. Nitrous oxide, on the other hand, is the oldest anesthetic drug in use, mostly in dental offices. It’s extremely safe, inexpensive and easy to administer.”
Unlike the ‘laughing gas’ image of euphoria, test subjects did not get high on the treatment. Nagele and the team find this pilot an exciting first step, but they need a larger study. In some patients, the antidepressant effects lasted a week. Because oral anti-depression medications can take four to six weeks to be fully effective, Nagele says nitrous oxide also could serve as a bridge therapy to control symptoms while the standard oral antidepressant effects kick in, especially in suicidal patients.
[personalized cancer vaccines]
Washington University is developing personalized treatment strategies for different cancers. Cancer vaccines can be developed by knowing the patient’s unique mutations. That is done by taking samples of cancerous and normal tissue from the patient and sequencing the genomes of both to identify the mutated proteins called neoantigens unique to that person’s tumor cells. Then, using computer algorithms and laboratory tests, the researchers can predict and test which of those neoantigens would be most likely to stimulate a potent immune response by the patient’s T-cells and include those in a vaccine.
A recent test reported in Science Express had a trial of six patients with metastatic melanoma, an invasive skin cancer. Data on the first three patients was reported in the paper. Says Dr. Gerald Linette, a WU medical oncologist at Siteman Cancer Center and Barnes-Jewish Hospital, “This proof-of-principle study shows that these custom-designed vaccines can elicit a very strong immune response.”
Melanomas typically have high numbers of genetic mutations, 500 or more, caused by exposure to sunlight. The vaccine designers identified those mutations expressed by the patient’s tumor that were most likely to be seen by the immune system as ‘non-self’ or alien. All three patients had experienced recurrent tumors after multiple surgeries. Each was given a unique vaccine with seven neoantigens, administered in three doses six weeks apart.
During the test, researchers did serial CT scans to observe the tumors over time. In general, the response was stabilization, so the tumors weren’t growing and the patients felt well enough to be back at work. The purpose of the study was to show they could identify the correct neoantigens, develop a personalized vaccine and observe an immune response. This is the first melanoma vaccine in the world to demonstrate an effect. Linette and the vaccine team are working on improvements in the vaccine and plan to open a larger, multi-center trial.
[less-invasive brain surgery]
Saint Louis University neurosurgeons are using a new smaller incision for surgical access and imaging during some brain surgeries. Called BrainPath technology, it allows surgeons to reach deep-seated tumors or intracranial hemorrhage through a dime-sized incision rather than opening a large section of the skull. SLUCare neurologist Dr. Jeroen Coppens says the new technology offers safer access. Via the small incision, he can place a small tube into the brain, moving past natural brain folds and fibers without cutting through them. Then using a camera inserted in the tube, he can see brain structures in high definition and avoid them while cutting out a tumor.
Neurosurgeons at SLU have been using the technology for a year now and have been building experience. One area it’s useful for is in treating intracranial hemorrhages, says Coppens. “These hemorrhages are usually deep in the brain, and open surgical results haven’t been great,” he notes. “With BrainPath, we can use a different trajectory, going in above the eyebrow deep into the brain. By intervening early, we can decrease hematoma formation and stop cascade effects and morbidity.”
Functional MRI imaging can show the tract in the brain to guide the cannula and let the surgeons know in real time how deep they are going. Once the cannula is docked, they can bring in an exoscope (camera) to zoom in for a perfect view on a large screen and do very precise work, Coppens reports.
[gentler valve repair]
Leaky mitral valves can cause blood to flow backward into the upper chamber of the heart, creating debilitating symptoms like fatigue and shortness of breath. Over time, it can lead to abnormal heart rhythms, blood clots and even infection of the heart valve. Until recently, open heart surgery was the preferred choice to repair or replace the faulty valve.
Saint Louis University Hospital offers the MitraClip option for patients who aren’t good surgical candidates. This device is inserted via a catheter threaded through a vein, nonsurgically. Under imaging guidance, the clip can be attached to the non-closing leaflets of the valve to greatly reduce the backflow. Dr. Richard Lee, co-director of the Center for Comprehensive Cardiovascular Care (C4) and a SLUCare physician, says MitraClip patients showed improvement in symptoms and reduced hospitalizations for heart failure. “When the valve expands and dilates, two leaflets squish together to keep blood flowing in one direction. When they don’t do that, blood flows backward. We essentially create two small valves instead of one big one, by pinching the leakage area together to decrease regurgitation. Results of a randomized study show that it accomplished what we wanted and holds over a period of time, at least two years so far.”
He says if a patient is at increased risk for open-heart surgery, has had a previous bypass, or has bad kidneys or lungs, they get the MitraClip. It is FDA-approved for high-risk patients and still in studies for other patients.
[alzheimer’s forewarnings]
In Alzheimer’s treatment, identifying the condition early enough for medications to forestall the disease is optimal. Pinpointing time of origin for symptoms like depression, irritability, apathy and appetite loss could help researchers find ways to counteract them.
Catherine Roe, Ph.D., assistant professor of neurology at Washington University School of Medicine, says there is conflicting evidence on the relationship of Alzheimer’s and symptoms like depression. She says they don’t know if people exhibit these symptoms because they realize on some level that they are having cognitive problems, or whether the symptoms are early indicators of the disease itself.
Roe and her colleagues at the Alzheimer’s Disease Research Center analyzed data on 2,416 people aged 50 and older who had been followed for up to seven years by the center. All were normal at the start, but half developed Alzheimer’s. When they were matched with normal counterparts, those who developed the dementia disease were more likely to have mood and behavioral changes first. For example, four years into the study, 30 percent of those who would develop Alzheimer’s had depression, compared with only 15 percent of those who did not develop the dementia.
While these findings are not a basis for changing treatment protocols, they alert doctors to watch out for subtle changes and try to determine the cause. Many things can cause depression or lack of appetite besides impending dementia, but Roe says it puts us on alert about early signs that can be tied to dementia and might make treatment in the future more proactive.
