Discovery

Restoring Power: New Therapies for Neurodegenerative Diseases

by Jaron Terry, APR

With internationally renowned experts in virtually every area of the neurosciences – in laboratories, clinics and operating rooms – Ohio State’s Neurosciences Signature Program is developing and testing promising new therapies for neurodegenerative diseases such as Parkinson’s, Alzheimer’s and Huntington’s. And just in time. The incidence of these diseases is expected to increase dramatically over the next 40 years.

Everyone misplaces their car keys or eyeglasses from time to time. Many are sometimes awakened in the night by muscle spasms. For most people, such incidents are no cause for alarm. For others, they may signal the beginning of a neurodegenerative disorder that will affect their neurological well-being – and the lives of their friends and loved ones – in significant ways.

At Ohio State, investigators are moving forward on several fronts to determine the causes and courses of neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s, as well as spinal muscular atrophy and others. Their promising translational research is focused not only on the prevention and early detection of such debilitating conditions, but also on discovering ways to treat the symptoms, thereby improving the quality of life for individuals who have them.

According to E. Antonio Chiocca, MD, PhD, world-renowned neurosurgeon and physician-scientist who leads Ohio State’s Neurosciences Signature Program, each of these diseases – which are only four in a wide spectrum of neurodegenerative diseases – has one thing in common.

“In each case, the underlying cause is the death of neurons. The resulting array of symptoms that differ from one disease to another depends on in which area of the brain or spine the neurons die,” explains Chiocca, who also is professor and chair of Ohio State’s Department of Neurological Surgery.

“Although our brains are superior to computers in many ways, if one thinks of neurons as computer chips, one can better understand that each neuron – each individual nerve cell – has a specific function. But, it is the cyclical and coordinated electrical activity among groups of neurons located in different parts of the brain that makes us think, remember, move in certain ways and, in fact, makes us human,” he asserts.

“When these ‘molecular chips’ die prematurely, the resulting cost is huge in terms of lost work hours, lost relationships, loss of control over body functions and the beginning of a long, slow decline to death,” Chiocca explains. “That is why investigators are working so hard, collaborating with their colleagues here at Ohio State and around the world, to make discoveries that may stop these diseases from occurring and to develop innovative new treatments for those who are suffering now.”

Promises to Keep: Alzheimer’s Breakthroughs

A devastating memory- and personality-robbing disease that turns families upside-down, Alzheimer’s disease (AD) – the result of plaques and neurofibrillary tangles distributed throughout the cerebral cortex – is somewhat responsive to certain medications when prescribed in the earliest stages.

“Unfortunately, the benefits of medication are sometimes delayed because lack of self-insight and family member denial keep many Alzheimer’s patients from seeking diagnosis and treatment, sometimes for as long as three or four years after the initial symptoms,” says neurologist Douglas Scharre, MD, associate professor and director of the Division of Cognitive Neurology in Ohio State’s Department of Neurology.

Scharre developed a screening test that he hopes will shorten the time between first symptoms and access to treatment. Dubbed SAGE (Self-Administered Gerocognitive Examination), the pencil-and-paper test has proven to be a useful predictor of cognitive dysfunction and represents a major breakthrough in Alzheimer’s care.

Scharre also is leading Ohio State’s involvement in a multicenter study of the effects of a vaccine-like treatment in delaying or slowing the course of AD.

“With approximately 5 million people suffering from AD and the number of cases rising, it is increasingly important to prevent progression of the disease. Studies have shown that delaying the onset for five years would result in a 50-percent reduction in the number of cases,” he explains. The study involves a drug designed to remove a protein that accumulates in the brains of individuals with AD.

Huntington’s Findings

Characterized by behavioral and mood changes, motor problems and cognitive difficulties, Huntington’s disease (HD) is the result of neuron death in the basal ganglia and other subcortical and cortical structures in the brain.

Sandra Kostyk, MD, PhD, medical director of the Huntington’s Disease Society of America Center of Excellence at The Ohio State University, has just completed participation in a major national study, PHAROS (Prospective Huntington’s At-Risk Observational Study), to identify the earliest symptoms of HD.

Ohio State’s principal investigator for this multicenter study of more than 1,000 at-risk persons, Kostyk explains that the purpose of the study is to identify clinical markers of the disease and disease-modifying factors such as diet, history of head injury, spiritual practices, exercise habits and other factors that may be related to onset of the disease.

“Because Huntington’s is an autosomal dominant disorder, children born to persons with HD have a 50 percent chance of manifesting the disease,” she notes. “Through a simple gene test, we can know from day one if someone will develop HD. However, many people do not want to get tested for a variety of reasons. We are searching to define early symptoms of clinical onset so treatment can begin.” Data from all study sites are being compiled and analyzed by the Clinical Trials Research Center at the University of Rochester, with findings expected to be published thereafter.

Ohio State Welcomes Ali Rezai, MD

Ali Rezai, MD, joined The Ohio State University faculty this summer as professor and vice chair for Clinical Research for the Department of Neurological Surgery, Director of Ohio State’s Center for Neuromodulation and director of the Functional Neurosurgery Program. He was previously the director of the Center for Neurological Restoration and professor of Neurosurgery at The Cleveland Clinic.

Dr. Rezai will be working to develop the neuromodulation program at Ohio State, which involves the implanting of neurological pacemakers and micro-infusion devices into the brain, spinal cord and other nerves to treat movement disorders, epilepsy, stroke, headache, pain and psychiatric disorders. He has published more than 100 peer-reviewed articles, led seven NIH grants and has been interviewed widely in national media on the subject of deep brain stimulation. Dr. Rezai also holds 13 U.S. patents.

Parkinson’s Discoveries

In Parkinson’s disease (PD), neurons inexplicably die in a region of the brain called the substantia nigra, which controls body movement. The result is significant motor disruptions, with persons at first experiencing slight muscle spasms or tremors, then difficulty grasping objects and, finally, the inability to walk, swallow or breathe. Dementia associated with Parkinson’s (Dementia with Lewy Bodies) has an insidious, slow onset and is usually accompanied by apathy and depression. Generally, this nonhereditary disease occurs in mid-to-late life and is unpredictable.

“Although we still don’t fully understand why neurons die in PD, we’re working to develop a gene-transfer therapy to replace a particular protein that is no longer available once neurons die,” says Matthew During, MD, PhD, professor of Neurological Surgery and of Molecular Virology, Immunology and Medical Genetics (MVIMG).

“Gene-transfer therapy basically provides a new blueprint for cells to follow, as it changes faulty chemistry within the brain. By physically inserting a replacement gene, we are
reinstructing cells to create a certain protein – GAD – that helps reset the circuitry and control movement,” he explains.

During, who oversees the Neuroscience Program in Ohio State’s MVIMG department, pioneered the approach and is working on a clinical trial in collaboration with Atom Sarkar, MD, PhD, assistant professor of Neurological Surgery and of Chemical and Biomolecular Engineering.

“It’s a little bit like Fantastic Voyage, but without the girl,” chuckles Sarkar, a world-class neurosurgeon. “While the patient is awake, I access the affected part of the brain and, using a specialized needle, deliver a gene directly into the critical area.”

In addition, Sarkar, who is director of Neurological Nanomedicine, has been successfully treating PD patients with deep brain stimulation (DBS). DBS delivers electrical pulses directly to brain tissue that controls movement. The surgery dramatically reduces tremors or problems of rigidity in patients with PD by interrupting the signals that cause them.

“It’s the closest thing we have to magic in neurosurgery and is most effective when used early on in the disease process,” he adds.

The recent recruitment of world-renowned neurosurgeon Ali Rezai, MD, from The Cleveland Clinic has dramatically expanded Ohio State’s DBS capabilities. Rezai is one of the nation’s leading surgeons and media spokespeople on the use of DBS to treat Parkinson’s disease, Tourette’s syndrome, obsessive compulsive disorders and other neurological conditions.

Spinal Muscular Atrophy Progress

“The most fatal genetic disease in infants is spinal muscular atrophy (SMA), but it is relatively unknown among the general public because the majority of those born with it die before the age of 2,” says John Kissel, MD, professor of Neurology, director of the Division of Neuromuscular Medicine and co-director of the SMA Clinic at Ohio State and Nationwide Children’s Hospital.

In SMA, motor neurons in the spinal cord die due to a lack of a specific protein, SMN. In the most debilitating form, infants quickly lose the ability to swallow or breathe; another form renders children unable to stand or walk.

“The $64,000 question is, what exactly does the SMN protein do and how can researchers uncover a way to replace or replicate it?” says Kissel. “Nearly 20 years ago, Dr. Arthur Burghes began work at Ohio State to identify the gene involved in SMA and the molecular pathogenesis of the disorder. Today, a number of Ohio State investigators, including Drs. Tom Prior, Christine Beattie, Stephen Kolb, Brian Kaspar and many, many others, and I have been involved in studies ranging from basic science research to clinical trials in an effort to prevent this disease from claiming more young lives,” Kissel says.

“Our main focus right now is trying to find ways to ‘turn on’ or up-regulate a gene called SMN2, which is a kind of spare copy of the main SMN gene. We are currently doing two human clinical trials with drugs that seem to help cells produce more SMN2 and have been shown to be effective in mouse models of the disease. Dr. Kaspar’s laboratory is developing ways to genetically modify SMN expression to try to treat this disease.”

Future Promise

Michael Racke, MD, chair of Ohio State’s Department of Neurology, notes that experts at Ohio State, already internationally recognized for their advances, continue to push the boundaries of discovery and care for neurodegenerative and related diseases.

“The Neurosciences Signature Program, under Dr. Chiocca’s direction, encompasses a wide array of excellent clinical programs – both medical and surgical – groundbreaking research projects, and highly sought fellowship and residency programs that train tomorrow’s experts,” Racke says.

“All of this innovative activity goes a long way toward advancing Ohio State’s mission to improve people’s lives by creating the future of medicine,” he adds.

Story Summary

There are many neurodegenerative diseases, but common to all is the death of neurons. Symptoms differ based on where in the brain or spine neuron death occurs.
Five million people suffer from Alzheimer’s disease in the United States, and the numbers are rising. Research and therapies today focus on trying to delay its onset.
Promising research in Parkinson’s disease at Ohio State focuses on gene transfer therapies and deep brain stimulation, which dramatically reduces tremors and rigidity.