Physician’s Brief clinical and research highlights for our colleagues in neurology and neurosurgery Ye a r- E n d 2014
A One-Two Punch for Brain Tumors? New gene therapy trial opens at U-M University of Michigan doctors have started testing a unique new approach to fighting brain tumors -- one that delivers a one-two punch designed to knock out the most dangerous brain cancer. The experimental approach, based on U-M research, delivers two different genes directly into the brains of patients following the operation to remove the bulk of their tumors. The idea: trigger immune activity within the brain itself to kill remaining tumor cells -- the ones neurosurgeons can’t take out, which make this type of tumor so dangerous. It’s the first time this gene therapy approach is being tried in humans, after more than a decade of research in experimental models. Three patients have already been treated as part of the trial. One of the genes is designed to kill tumor cells directly, and is turned on when the patient takes a certain drug. The other gene spurs the body’s own immune system to attack remaining cancer
cells. Both are delivered into brain cells via a harmless virus. All patients in the study must have a presumptive diagnosis of WHO grade 3 or 4 malignant primary glioma, such as glioblastoma multiforme; patients must not have been treated yet by any therapy. They must also meet other criteria for inclusion in the trial. More patients will be able to enroll at a pace of about one every three weeks, through a careful selection process. In addition to surgery and gene therapy at U-M, each will receive standard chemotherapy and radiation therapy as well as follow-up assessments for up to two years. “We’re very pleased to see our years of research lead to a clinical trial, because based on our prior work we believe this combination of cell-killing and immunestimulating approaches holds important promise,” says principal investigator Pedro Lowenstein, M.D., Ph.D., the U-M Department of Neurosurgery professor who
Maria Castro, Ph.D., and Pedro Lowenstein, M.D., Ph.D.
has co-led the basic research effort to develop and test the strategy. Co-leader Maria Castro, Ph.D., notes that the patients who agree to take part in the Phase I trial will be the first in the world to help establish the safety of the approach in humans. “Without them, and without our partners on the U-M Neurosurgery team and donors to the Phase One Foundation that support our work, we wouldn’t be able to take this important step in testing this novel therapeutic approach.”
For more about the trial, visit http://umhealth.me/gliomatrial or call 1-800-865-1125.
Taking Stroke Care to the Next Level In June, the University of Michigan Health System received certification as a Comprehensive Stroke Center by the Joint Commission and was recognized by the American Heart Association and American Stroke Association. Less than 100 other hospitals in the country have achieved this elite status. The new designation means U-M’s Comprehensive Stroke Center offers a highly trained team and technologies for patients before, during and after suffering a stroke. Led by stroke neurologist Eric Adelman, M.D., neurosurgeon Aditya S. Pandey, M.D., and emergency medicine physician William Meurer, M.D., the stroke team also includes neurologists, neurosurgeons, emergency medicine physicians, neurointerventional radiologists, physiatrists, vascular surgeons, neurointensivists, internists, nurse practitioners, physical and occupational therapists, speech and language pathologists and other staff specifically trained in stroke care. They have trained and prepared to act together; giving each patient the best options for treatment from the moment they arrive. This includes the ability to rapidly diagnose what is causing each patient’s stroke symptoms, using advanced medical imaging and minimally invasive procedures in the area’s only neurointerventional radiology suite when necessary. They are also able to deliver time-critical treatments and procedures to dissolve blood clots in the brain, to remove
stubborn clots or to repair the source of bleeding in the brain.
high-quality stroke care provided at the University of Michigan.”
“The spectrum of what we offer and the way we incorporate the latest knowledge into our clinical care truly set us on a level with few other centers in the country,” says Adelman, an assistant professor in the U-M Department of Neurology. “Our multidisciplinary approach ensures that our patients and their families receive the highest level of care.”
Because U-M researchers also study stroke and coordinate national and statewide stroke care improvement studies, patients who come to UMHS for stroke care also receive treatment based on the latest research – and often have access to clinical trials of new options that few other hospitals offer.
The certification also means advanced care beyond the crucial first hours after a stroke strikes – including inpatient care within University Hospital and the Frankel Cardiovascular Center, individualized rehabilitation and outpatient care once stroke survivors have left the hospital, and top care for patients at high risk of a stroke. “It takes a strong team to give a stroke patient absolutely optimal care, and that’s what we aim to do,” says Pandey, an assistant professor in the U-M Department of Neurosurgery who specializes in minimally invasive brain procedures for patients having or at high risk of a stroke. “The outcomes our patients achieve and the number of stroke patients we treat are the true indicators of the
Stroke is the leading cause of longterm disability and the fourth leading cause of death in the United States. A stroke occurs every 45 seconds and stroke causes a death every 4 minutes.
For a consult with a member of the Comprehensive Stroke Center or to inquire about a transfer, call M-LINE at 800-962-3555.
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800-962-3555 Your physician-to-physician connection to over 3,000 U-M doctors and 26 departments, 24 hours a day.
Epilepsy in a Dish A novel stem cell-based approach to studying epilepsy has yielded a surprising discovery about what causes one form of the disease, and may help in the search for better medicines to treat all kinds of seizure disorders. The technique, pioneered by a team of scientists from U-M and the Cleveland Clinic, could be called “epilepsy in a dish”. By turning skin cells of epilepsy patients into stem cells, and then turning those stem cells into neurons, the team created a miniature testing ground for epilepsy. They could even measure the signals that the cells were sending to one another, through tiny portals called sodium channels. In neurons derived from the cells of children who have a severe, rare genetic form of epilepsy called Dravet syndrome, the researchers reported abnormally high levels of sodium current activity. They saw spontaneous bursts of communication and “hyperexcitability” that could potentially set off seizures. Neurons made from the skin cells of people without epilepsy showed none of this abnormal activity. The team’s findings differ from what other scientists have seen in mice — demonstrating the importance of studying cells made from human epilepsy patients. Because the cells came from patients, they contained the hallmark seen in most patients with Dravet syndrome: a new mutation
in SCN1A, the gene that encodes the crucial sodium channel protein called Nav1.1. That mutation reduces the number of channels to half the normal number in patients’ brains. “With this technique, we can study cells that closely resemble the patient’s own brain cells, without doing a brain biopsy,” says team leader Jack M. Parent, M.D., professor of neurology at U-M and a researcher at the VA Ann Arbor Healthcare System. “It appears that the cells are overcompensating for the loss of channels due to the mutation. These patient-specific induced neurons hold great promise for modeling seizure disorders, and potentially screening medications.”
A platform for testing medications Many Dravet patients don’t respond to current epilepsy medications, making the search for new options urgent. Their lives are constantly under threat by the risk of SUDEP, sudden unexplained death in epilepsy – and they never outgrow their condition, which delays their development and often requires round-the-clock care. The team, which also includes Miriam Meisler, Ph.D., a professor in the U-M Department of Human Genetics and Lori Isom, Ph.D., a professor in the U-M Department of Pharmacology, is now working toward screening specific compounds for seizure-calming
Jack Parent, M.D.
potential in Dravet syndrome, by testing their impact on the cells in the “epilepsy in a dish” model. The National Institutes of Health has made a library of drugs that have been approved by the U.S. Food and Drug Administration available for researchers to use — potentially allowing older drugs to have a second life treating an entirely different disease from what they were initially intended. Having a U-M team that includes experts in induced pluripotent stem cell biology, sodium channel physiology and epilepsy genetics helps the research progress, Parent notes. “Epilepsy is a complicated brain network disease,” he says. “It takes team-based science to address it.”
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University of Michigan Health System Department of Neurology Department of Neurosurgery David J. Fink, M.D., Chair
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The Regents of the University of Michigan
Michael M.E. Johns, M.D., Interim Executive Vice President for Medical Affairs; James O. Woolliscroft, M.D., Dean, U-M Medical School; T. Anthony Denton, J.D., MHA, Acting Chief Executive Officer, U-M Hospitals and Health Centers; Kathleen Potempa, Ph.D., Dean, School of Nursing.
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