BY STEPHANIE STEMMLER
Janice E. Brunstrom-Hernandez, MD, director of the Pediatric Neurology Cerebral Palsy Center,
with patient Bryn Adams and her dad, Keith.
The number of people affected by degenerative brain diseases is growing as the population ages, while mental illness affects 1 in 4 adults and 1 in 5 children in the United States. In multiple ways, we see the physical, emotional, and financial toll of brain disorders and diseases upon society.
Our researchers have developed a highly accurate diagnostic tool for autism and are homing in on the disease’s genetic triggers. We are leading worldwide clinical trials to test new drugs that may prevent or halt the progression of Alzheimer’s disease and dementia. Investigators at Washington University are leading a coalition of scientists who are undertaking the effort to map the human brain.
At the School of Medicine, there is a confluence of research expertise and a rich legacy of pioneering advances in neurosciences that goes back more than 50 years. Diverse collaborations are underway in fields such as neurosurgery and neurology, psychiatry, neuroimaging, molecular biology, and pathology — all trying to unravel the enigma that is the human mind and brain.
The field of neurosciences is poised to make significant medical advances over the next two decades. With your support, we can lead the way in this important area of research and clinical care.
An investigational treatment for an inherited form of Lou Gehrig’s disease has passed an early phase clinical trial for safety, researchers at Washington University School of Medicine in St. Louis and Massachusetts General Hospital report.
The researchers have shown that the therapy produced no serious side effects in patients with the disease, also known as amyotrophic lateral sclerosis (ALS). The phase 1 trial’s results, available online in Lancet Neurology, also demonstrate that the drug was successfully introduced into the central nervous system.
The treatment uses a technique that shuts off the mutated gene that causes the disease. This approach had never been tested against a condition that damages nerve cells in the brain and spinal cord.
“These results let us move forward in the development of this treatment and also suggest that it’s time to think about applying this same approach to other mutated genes that cause central nervous system disorders,” says lead author Timothy Miller, MD, PhD, assistant professor of neurology at Washington University. “These could include some forms of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and other conditions.”
ALS destroys nerves that control muscles, gradually leading to paralysis and death. For treatment of the disease, the sole FDA-approved medication, Riluzole, has only a marginal effect.
Most cases of ALS are sporadic, but about 10 percent are linked to inherited mutations. Scientists have identified changes in 10 genes that can cause ALS and are still looking for others.
The study focused on a form of ALS caused by mutations in a gene called SOD1, which account for 2 percent of all ALS cases. Researchers have found more than 100 mutations in the SOD1 gene that cause ALS.
“At the molecular level, these mutations affect the properties of the SOD1 protein in a variety of ways, but they all lead to ALS,” says Miller, who is director of the Christopher Wells Hobler Lab for ALS Research at the Hope Center for Neurological Disorders at Washington University.
Rather than try to understand how each mutation causes ALS, Miller and his colleagues focused on blocking production of the SOD1 protein using a technique called antisense therapy.
To make a protein, cells have to copy the protein-building instructions from the gene. Antisense therapy blocks the cell from using these copies, allowing researchers to selectively silence individual genes.
“Antisense therapy has been considered and tested for a variety of disorders over the past several decades,” Miller says. “For example, the FDA recently approved an antisense therapy called Kynamro for familial hypercholesterolemia, an inherited condition that increases cholesterol levels in the blood.”
Miller and colleagues at the University of California-San Diego devised an antisense drug for SOD1 and successfully tested it in an animal model of the disease.
Merit Cudkowicz, MD, chief of neurology at Massachusetts General Hospital, was co-PI of the phase I clinical safety trial described in the new paper. Clinicians at Barnes-Jewish Hospital, Massachusetts General Hospital, Johns Hopkins Hospital and the Methodist Neurological Institute in Houston gave antisense therapy or a placebo to 21 patients with SOD1-related ALS. Treatment consisted of spinal infusions that lasted 11 hours.
The scientists found no significant difference between side effects in the control and treatment groups. Headache and back pain, both of which are often associated with spinal infusion, were among the most common side effects.
Immediately after the injections, the researchers took spinal fluid samples. This let them confirm the antisense drug was circulating in the spinal fluid of patients who received the treatment.
To treat SOD1-related ALS in the upcoming phase II trial, researchers will need to increase the dosage of the antisense drug. As the dose rises, they will watch to ensure that the therapy does not cause harmful inflammation or other side effects as it lowers SOD1 protein levels.
“All the information that we have so far suggests lowering SOD1 will be safe,” Miller says. “In fact, completely disabling SOD1 in mice seems to have little to no effect. We think it will be OK in patients, but we won’t know for sure until we’ve conducted further trials.”
The therapy may one day be helpful in the more common, noninherited forms of ALS, some of which may be linked to problems with the SOD1 protein.
“Before we can consider using this same therapy for sporadic ALS, we need more evidence that SOD1 is a major contributor to these forms of the disorder,” Miller says.
The trial was conducted with support from ISIS Pharmaceuticals, which co-owns a patent on the SOD1 antisense drug.
Miller TM, Pestronk A, David W, Rothstein J, Simpson E, Appel SH, Andres PL, Mahoney K, Allred P, Alexander K, Ostrow LW, Schoenfeld D, Macklin EA, Norris DA, Manousakis G, Crisp M, Smith R, Bennett CF, Bishop KM, Cudkowicz ME. An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised first-in-man study. Lancet Neurology, online May 29, 2013.
The clinical trial was funded by the Muscular Dystrophy Association, the ALS Association and Isis Pharmaceuticals.
Sleep is disrupted in people who likely have early Alzheimer’s disease but do not yet have the memory loss or other cognitive problems characteristic of full-blown disease, researchers at Washington University School of Medicine in St. Louis report March 11 in JAMA Neurology.
The finding confirms earlier observations by some of the same researchers. Those studies showed a link in mice between sleep loss and brain plaques, a hallmark of Alzheimer’s disease. Early evidence tentatively suggests the connection may work in both directions: Alzheimer’s plaques disrupt sleep, and lack of sleep promotes Alzheimer’s plaques.
“This link may provide us with an easily detectable sign of Alzheimer’s pathology,” says senior author David M. Holtzman, MD, the Andrew B. and Gretchen P. Jones Professor and head of Washington University’s Department of Neurology. “As we start to treat people who have markers of early Alzheimer’s, changes in sleep in response to treatments may serve as an indicator of whether the new treatments are succeeding.”
Sleep problems are common in people who havesymptomatic Alzheimer’s disease, but scientists recently have begun to suspect that they also may be an indicator of early disease. The new paper is among the first to connect early Alzheimer’s disease and sleep disruption in humans.
For the new study, researchers recruited 145 volunteers from the University’s Charles F. and Joanne Knight Alzheimer’s Disease Research Center. All of the volunteers were 45 to 75 years old and cognitively normal when they enrolled.
As a part of other research at the center, scientists already had analyzed samples of the volunteers’ spinal fluids for markers of Alzheimer’s disease. The samples showed that 32 participants had preclinical Alzheimer’s disease, meaning they were likely to have amyloid plaques present in their brains but were not yet cognitively impaired.
Participants kept daily sleep diaries for two weeks, noting the time they went to bed and got up, the number of naps taken on the previous day, and other sleep-related information.
The researchers tracked the participants’ activity levels using sensors worn on the wrist that detected the wearer’s movements.
“Most people don’t move when they’re asleep, and we developed a way to use the data we collected as a marker for whether a person was asleep or awake,” says first author Yo-El Ju, MD, assistant professor of neurology. “This let us assess sleep efficiency, which is a measure of how much time in bed is spent asleep.”
Participants who had preclinical Alzheimer’s disease had poorer sleep efficiency (80.4 percent) than people without markers of Alzheimer’s (83.7 percent). On average, those with preclinical disease were in bed as long as other participants, but they spent less time asleep. They also napped more often.
“When we looked specifically at the worst sleepers, those with a sleep efficiency lower than 75 percent, they were more than five times more likely to have preclinical Alzheimer’s disease than good sleepers,” Ju says.
Ju and her colleagues are following up with studies in younger participants who have sleep disorders.
“We think this may help us get a better feel for the way this connection flows — does sleep loss drive Alzheimer’s, does Alzheimer’s lead to sleep loss, or is it a combination?” Ju says. “That will help us determine whether we can change the course of disease with pharmaceuticals or other treatments.”
The School of Medicine’s Bradley L. Schlaggar, MD, PhD, has been awarded the E. Mead Johnson Award for Pediatric Research.
Bradley L. Schlaggar, MD, PhD, the A. Ernest and Jane G. Stein Professor of Neurology at Washington University School of Medicine in St. Louis, has been awarded the E. Mead Johnson Award for Pediatric Research.
The award, among the most prestigious in pediatric research, is given by the Society for Pediatric Research for outstanding research achievements in pediatrics. Schlaggar, who is also on staff at St. Louis Children’s Hospital, is being honored for his contributions to basic and translational research using brain imaging, such as functional MRI, to understand the development of human cognition.
“Dr. Schlaggar has made tremendous contributions to the study of developmental cognitive neuroscience,” says Alan L. Schwartz, MD, PhD, chairman of the university’s Department of Pediatrics. “We are pleased his outstanding efforts are being recognized with such an esteemed award.”
Schwartz and Larry J. Shapiro, MD, executive vice chancellor for medical affairs and dean of the School of Medicine, nominated Schlaggar for the honor. Schwartz and Shapiro are both previous winners of the E. Mead Johnson Award.
Schlaggar’s research has advanced the understanding of cognitive development in children. He has created and implemented cutting-edge functional neuroimaging methods to investigate basic mechanisms in the development of language, reading, attention and executive control. Schlaggar has investigated these issues in healthy children and those whose cognitive skills are delayed by strokes or illness, including Tourette Syndrome.
Further, he and his colleagues have used advanced computational tools with functional MRI data to make predictions about individual children, including the functional maturity of a child’s brain or whether he or she has a particular neurologic diagnosis. The ability to use information in a brain scan to say something specific about an individual is critically important for using functional MRI as a clinical tool.
Schlaggar — who is also a professor of pediatrics, radiology, and anatomy and neurobiology — will receive the award in May at the Pediatric Academic Societies annual meeting in Washington.
Schlaggar came to Washington University School of Medicine in 1986 for the MD/PhD program. He remained at the university for a pediatric neurology residency and fellowship, and joined the faculty in 1999.
Schlaggar is also director of the Pediatric Neurology Residency Training Program at the School of Medicine and St. Louis Children’s Hospital, director of the university’s Pediatric Movement Disorder Program and associate director of the Division of Pediatric and Developmental Neurology.
Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.