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UAB implants responsive neurostimulator for epilepsy seizure control, first in Southeast

On June 18, neurosurgeons at the University of Alabama at Birmingham implanted a new type of electrical stimulator to control seizures in patients with difficult-to-control epilepsy.

It marked the first time in the Southeast the RNS system by NeuroPace had been implanted since the device gained FDA approval in November 2013. The first patient was a 24-year-old woman from central Alabama.

RNS stands for responsive neurostimulation.

“It is designed to record patient’s specific brain activity and recognize patterns that are associated with seizures,” said Kristen Riley, M.D., associate professor in the Department of Neurosurgery. “The RNS system then delivers stimulation in order to help modulate and control the seizures.”

The system consists of electrodes attached by leads to a generator which can communicate with a computer. The generator is curved so that it can be placed within a patient’s skull. It is a little bigger than a flash drive.

“We drill a trough for the device so that it is flush within the skull,” said Riley. “There is not a raised area; it’s basically hidden within the skull.”

The RNS system is for patients with severe seizures who do not respond to medications and are not candidates for surgery because the location of their seizure onset is at a sensitive part of the brain. It is also only for patients whose seizure onset can be traced to just one or two locations in the brain.
The electrodes are placed near the location in the brain where a patient’s seizures are triggered. Jerzy Szaflarski, M.D., Ph.D., professor in the Department of Neurology and director of the UAB Epilepsy Center, says the RNS system can be customized for each individual patient so that it learns which patterns of brain activity lead to seizures in that patient. He says data from research studies dating back several years indicate that many patients will respond to the stimulation and have significant reduction in their seizures.

“This is not a treatment that will cure epilepsy,” he said. “This is a treatment that will help control seizures in a very specific group of patients who are not otherwise candidates for surgery. I don’t expect too many patients to become seizure-free; but if we can decrease their seizures by even half, we can make huge improvements in their lives.”

The RNS system is for patients with severe seizures who do not respond to medications and are not candidates for surgery because the location of their seizure onset is at a sensitive part of the brain. It is also only for patients whose seizure onset can be traced to just one or two locations in the brain.

“We’re very excited to offer this therapy to our patients who are not candidates for more traditional therapies for epilepsy,” said Szaflarski. “We see multiple patients like that every year, and the RNS system could make a huge difference in the lives of those patients. There is already data to show that the quality of life of those patients has improved significantly with RNS.”

For more information on the RNS system, contact the UAB Epilepsy Center or make an appointment via the Kirklin Clinic at 205-801-8986.

Bob Shephard
UAB Media Relations

UAB launches three initiatives to stimulate personalized medicine care, research

June 16, 2014        

 

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  • The University of Alabama Board of Trustees approved the creation of the Personalized Medicine Institute, the Institute for Informatics and the UAB-HudsonAlpha Center for Genomic Medicine.
                           
    Three new initiatives in the University of Alabama at Birmingham School of Medicine are paving the way for significant growth and acceleration of personalized medicine in Alabama, the region and beyond.
    “UAB is one of the largest and most productive academic medical centers in the country, and the work accomplished through these initiatives will be transformative for Alabama and the nation. UAB will lead in these three areas.”  
    On Friday, June 13, 2014, the University of Alabama Board of Trustees approved the creation of the Personalized Medicine Institute, the Institute for Informatics and the UAB-HudsonAlpha Center for Genomic Medicine. All three programs will be housed in the School of Medicine, pulling together scientists and physicians from a variety of disciplines to bear on a multitude of diseases and disorders.
    “This is the future of medicine, and UAB wants to be on the leading edge,” said Selwyn M. Vickers, senior vice president for Medicine and dean of the School of Medicine at UAB. “UAB is one of the largest and most productive academic medical centers in the country, and the work accomplished through these initiatives will be transformative for Alabama and the nation. UAB will lead in these three areas.”

Genomic Medicine

In the UAB-HudsonAlpha Center for Genomic Medicine, faculty from UAB and HudsonAlpha will work together, on each institution’s campus, to create a platform for using human genome data and applying it to patient care. The  Center, co-directed by Bruce Korf, M.D., chair of the UAB Department of Genetics, and Rick Myers, Ph.D., president and science director of HudsonAlpha, combines UAB’s expertise in clinical genetics with HudsonAlpha’s concentration in genome research. Read more about the Center for Genome Medicine here.

Personalized Medicine

The Personalized Medicine Institute, or PMI, directed by Nita Limdi, Pharm. D., Ph.D., associate professor in the UAB Department of Neurology, will enhance the delivery of personalized medicine by using a patient’s own genetic makeup along with their clinical characteristics. This will allow more specific selection and dosing of medications, Limdi said.
Two main initiatives will drive the PMI: fueling discovery through research and improving patient care.
2010311041400.Limdi08Nita Limdi, Pharm.D., Ph.D.To fuel the research initiative, the PMI will create and manage a “bio bank,” a cache of DNA samples that will pay dividends as a resource for future research. “The BioBank will help speed progress toward personalized medical care and contribute to a better understanding of how genetic factors, lifestyles, behavior and environment can interact to affect a person’s health,” Limdi said. “Moreover, it will provide UAB researchers a tangible advantage when competing for grant funding, especially in areas where UAB serves unique populations.”
UAB’s continued success improving the health of minorities gives the School of Medicine, and Alabama, an advantage in research, Limdi said. For example, kidney transplant rates nationally are disproportionately low for African Americans. At UAB, one of the busiest kidney transplant centers in the country, more than half of all kidney transplants in the past 10 years were in African Americans.
“Most research centers don’t have this wealth of data about minority populations. This puts UAB at a competitive advantage to receive research grants, which will, in turn, improve the health of African Americans and other minorities,” Limdi said.
“The PMI will enhance the management of patients in large populations, create a research framework that will allow us to ask questions regarding racial and ethnic disparities, diabetes, cardiovascular disease, neurosciences and other areas, as well as expand our translational capacity for genomic discovery,” Limdi said. “This program will continually differentiate us from our local and regional peers and make us a national player in the development of new treatment therapies based on our understanding of the human genome.”
The patient care initiative will begin by identifying gene-drug and gene-disease targets for which genomics holds the potential to improve outcomes for patients. “Again, the population we serve allows us to evaluate the effectiveness of interventions in a racially diverse population,” Limdi said.
The School of Medicine will dedicated funds to the PMI to allow UAB to retain faculty and recruit new physicians and scientists, and to build an administrative infrastructure to facilitate more federal and private research grants. Educating physicians, trainees and the broader biomedical community, including bioethicists, is also an important component of the PMI to build partnerships in the general community and improve the overall health of the population, Limdi said.

Informatics

Underpinning personalized medicine and genomics is informatics – collecting, processing and making massive amounts of data available to researchers and clinicians in relevant, meaningful ways that advances research and improves patient care. According to a 2013 report by the United States Chamber of Commerce about “big data,” 90 percent of the data available in the world was produced in the previous two years. The National Institutes of Health created the “Big Data to Knowledge” initiative in order to “support the research, implementation and training of data science” to make data “a more prominent component of biomedical research.”  
The Personalized Medicine Institute, the Institute for Informatics and the UAB-HudsonAlpha Center for Genomic Medicine will be housed in the School of Medicine, pulling together scientists and physicians from a variety of disciplines to bear on a multitude of diseases and disorders.  
Fitting hand-in-glove with the NIH and other national initiatives, the UAB Informatics Institute will develop informatics in four key areas: data management; software expansion and development; bioinformatics, to support and propel medicine and health care specifically; and education of trainees and physicians to support research and clinical activities and train future informaticians, Vickers said.
“The UAB Informatics Institute will transform UAB into a learning healthcare system,” Vickers said.
The Institute of Medicine, of which Vickers is a member, began creating the “learning healthcare system” concept several years ago. Such a system is driven by the full gamut of data collected in clinical and research settings, from patient feedback and vital signs, to sequenced DNA of a particular type of tumor, to managing large populations of patients.
“In a learning healthcare system,” Vickers said, “data are continuously collected, shared, analyzed and used to propel clinical care, research and education.”
The School of Medicine will conduct a national search for a director of the Informatics Institute.

LRRK2 inhibitors may be key to combating Parkinson’s disease

An enzyme closely associated with genetic forms of Parkinson’s disease appears to play a larger role in its progression than previously thought, say UAB investigators. The new research offers encouraging evidence that drugs to block this enzyme, known as leucine-rich repeat kinase 2 or LRRK2, could slow — or even prevent — Parkinson’s from developing.In the study, published online in the Proceedings of the National Academy of Sciences June 4, UAB researchers eliminated the gene for LRRK2 (pronounced “lark two”) in rats and combined these animals with genetic models of Parkinson’s.

“We found that this offered very good protection from over-expression of a protein — alpha synuclein — that is linked to Parkinson’s disease,” said Andrew West, Ph.D., lead author on the paper and the John A. and Ruth R. Jurenko Endowed Professor in Neurology at UAB.

The genetic model used in the UAB study more closely mimics Parkinson’s disease than do other, more frequently used models, which suggests that inhibiting LRRK2 in humans could help more than those with the less-common genetic forms.

“The pool of Parkinson’s patients who might benefit from LRRK2 drugs may be bigger than we originally thought,” West said.

West’s lab is working closely with Birmingham-based Southern Research Institute through the Alabama Drug Discovery Alliance to rapidly develop LRRK2 inhibitors. He hopes to reach human testing as early as 2015.

Parkinson’s disease affects more than a million Americans. Tremors, stiff muscles and slow movement are the most common symptoms of the disease. These symptoms are caused by a massive loss of cells in the substantia nigra, a brain region that helps control movement. The dying cells are filled with clumps of alpha-synuclein, making it the chief suspect in Parkinson’s disease.

Refining the target

The trouble is that researchers have not found a way to control alpha-synuclein levels directly.

“It’s a normal protein — actually one of the most highly abundant proteins in the brain — so it isn’t easy to figure out how to block its progression into aggregates that spread through the brain,” West said.

That is why Parkinson’s researchers are so excited about LRRK2. In 2006, West demonstrated that all known mutations in LRRK2 increase LRRK2 activity. Other studies showed that LRRK2 is biochemically linked with alpha-synuclein in several ways.

Andrew West’s lab is working closely with Birmingham-based Southern Research Institute through the Alabama Drug Discovery Alliance to rapidly develop LRRK2 inhibitors. He hopes to reach human testing as early as 2015.
Since those discoveries in the rats, the idea has been that developing drugs to reduce LRRK2 activity should provide protection against damage caused by alpha-synuclein, according to West.

Genetic forms of Parkinson’s that have highlighted LRRK2 involvement in disease are widespread in some populations, including those of Ashkenazi Jewish and North African Berber descent, where inherited Parkinson’s accounts for up to 40 percent of cases.

“But it drops dramatically depending on your ethnic background,” West said. “If you’re from a European, Caucasian population, it’s more on the order of 2 to 3 percent. This may be important in initial first-in-man studies in deciding who should first get LRRK2 drugs.”

Advancing to human trials

Any treatment advance would be welcome in Parkinson’s, which West says has not seen a real breakthrough drug since L-dopa was developed 50 years ago.

“Together with Southern Research Institute, we have a very strong drug pipeline, and we hope to be in first-in-man studies as early as next year,” West said. “But while that work is ongoing, we need to ask a bigger question: What happens if you simply remove all LRRK2 activity? Modern approaches allow us to approximate what a perfect drug would do in rats and mice.”

The results, captured in the PNAS paper, emphasize the importance of LRRK2 and the need for further study, which West is pursuing.

“We think LRRK2 is plugging into Parkinson’s disease in more than one way,” West explained. “It is making the disease more likely to happen and making it progress faster when it does happen. So we think knocking out LRRK2 will do the opposite — slow the disease or make it much less likely to develop.”

Even slowing the disease marginally could have a tremendous effect on patients with Parkinson’s disease, West notes. Drugs like L-dopa are effective at controlling symptoms and making life manageable for patients; but they eventually stop working, and side effects inevitably become as burdensome as the disease itself, West says.

LRRK2 inhibitors could greatly extend the useful window for L-dopa treatment.

“Whereas L-dopa may be effective for 10 years currently, if LRRK2 inhibitors slowed disease progression, we could dramatically extend the effectiveness of existing drugs to 20, 30 or 40 years — basically the rest of the patient’s life.”

UAB neurologist edits first textbook on newly defined disease process

Anthony Nicholas, M.D., associate professor in the Department of Neurology at the University of Alabama at Birmingham, is a co-editor of the first textbook on the subject of protein deimination in human health and disease.Deimination is a process by which selected positively charged arginine amino acids are converted to neutral citrulline amino acids by the peptidyl arginine deiminase family of enzymes. The book is a comprehensive look at this rapidly developing field and illustrates the connection between deimination and numerous illnesses, including autoimmune diseases, Alzheimer’s, Parkinson’s, Creutzfeldt-Jakob disease, amyotrophic lateral sclerosis, cancer, periodontitis, glaucoma, spinal cord trauma and peripheral nerve injury.

Authors for each chapter of the book, titled “Protein Deimination in Human Health and Disease,” are international experts from the United States, Canada, Europe and Asia.

The publisher, Springer Publishing, said “‘Protein Deimination in Human Health and Disease’ is the first publication to compile this knowledge and the growing amount of new information now known about the presence of deiminated proteins in the eye, skin, hair, gums, lungs and nervous system, as well. Chronicling the earliest studies of deimination up to the present, this volume distills what is currently known about citrullination of proteins in the human body and is the first book of its kind on the topic.”