University of South Carolina

Designer genes target serious diseases


It's not surprising that neuroscientists in the School of Medicine are conducting research on epilepsy, Alzheimer's disease, neuropathic pain, cognition, mood disorders, and other nervous system-related conditions.

But it is extraordinary that all of them are using a similar gene therapy technique to blaze new trails of discovery. It's a technique made possible by a laboratory at the School of Medicine that engineers the key ingredients for gene therapy research used by neuroscientists around the world.

Marlene Wilson width=
Marlene Wilson

"We've had these core lab facilities for quite a while, and [lab director] Steve Wilson is recognized as one of the pioneers in developing this technology," said Marlene Wilson (no relation to Steve Wilson), a professor and chair of the Department of Pharmacology, Physiology, and Neuroscience.

Wilson and her colleagues in neuroscience all use common viruses that have been altered in special ways to deliver genetic instructions to a specific target -- either in the brain or the peripheral nervous system. The designer viruses are harmless but effective messengers of genetic material.

The gene transfer technique is allowing the neuroscientists to better understand the biochemical mechanisms associated with certain disorders and diseases. In some instances, they might be able to develop better targets for medications; in other cases, the gene therapy itself might introduce new ways of treating disease.

"There's a lot of effort going on now to make safe viral vectors for human delivery," Wilson said, "It's likely that gene transfer would initially be used for crippling disorders like degenerative diseases, chronic pain, and epilepsy. But it could be on the horizon to treat conditions such as severe anxiety and even depression disorders."


No pain, big gain

Every semester, Sarah Sweitzer tries to bring in at least one person who suffers with chronic neuropathic pain to speak to her medical students. Some can't work anymore, and most get no relief from traditional drug therapies. "They come to class and tell the students, ‘Doctors think I'm a drug addict,'" Sweitzer said. "They can't get any break from the pain."

Seventy-five million Americans suffer from chronic pain (lasting at least three to six months), expending billions on medications that often don't work, can become addictive, or have unpleasant side effects.

Neuropathic pain has many causes -- spinal cord injury, amputations, tumors pressing against nerves, and the aftermath of shingles (herpes zoster) infections, to name a few.

"With our system, you can turn on the body's own pain-reducing chemicals, so you would need fewer prescription drugs -- maybe none at all -- for pain control."

Sweitzer is using an altered form of the herpes simplex virus, which normally causes cold sores, to target neuropathic pain. The herpes virus naturally infects and resides in peripheral neurons that signal pain, and Sweitzer's customized virus does something more: it carries a genetic signal that activates the body's natural opioid-producing system.

"With our system, you can turn on the body's own pain-reducing chemicals, so you would need fewer prescription drugs -- maybe none at all -- for pain control," Sweitzer said. "If you think of pain as a loss of balance between excitatory pain causing activity and inhibitory pain suppressing activity, we're using these viruses to both decrease excitatory pain activity and increase pain suppressing activity."

A research group in Michigan is using similar strategies to address pain issues with terminally ill cancer patients. If that work shows results, it could open the door for more gene-therapy clinical trials for chronic pain sufferers using the unique viruses made at the School of Medicine.


Effects of aging

As if the usual insults of aging such as creaky knees and wrinkles weren't enough, it seems that old age also ushers in a reduction in an important neuropeptide called orexin (also known as hypocretin).

Orexin regulates sleep/wake cycles, cognition, and feeding and metabolism. People who suffer from narcolepsy (sudden periods of deep sleep throughout the day) have severely depleted orexin levels. Older people who experience unexplained weight loss are at higher risk for Alzheimer's disease: both might be linked to lower levels of orexin.

Jim Fadel is using a customized version of the common Lenti virus to target the hypothalamus, a region of the brain that makes orexin. His research, funded by the National Institute on Aging and American Federation for Aging Research, is testing the possibility of stimulating orexin production through virus-mediated gene therapy.

"Gene therapy started out with a lot of promise a couple of decades ago, but hit some snags. It has become a hot field again in neuroscience because of vast improvements in the ability to use specific promoters that target certain regions of the brain," Fadel said. "Our initial findings suggest virus-mediated orexin expression can improve the function of the cholinergic system, which we know plays a major role in Alzheimer's disease.

"I'm guessing that we're probably five years or more away from human trials with this particular research, but it could offer some very exciting possibilities in restoring cognitive function in those diagnosed with early-stage Alzheimer's."

The epileptic brain

After Alzheimer's disease and stroke, epilepsy is the third most common neurological disease.

David Mott
David Mott

It's also one of the more difficult to treat: Anticonvulsant drugs are effective for only 70 percent of those with the condition, and those drugs can cause many unwanted side effects. Treatment options for the other 30 percent range from few to none.

Funded by the National Institutes of Health, David Mott is studying the role of the excitatory neurotransmitter glutamate in epilepsy. Glutamate is used by 75 percent of all brain cells to communicate with each other. Mott is using a specialized virus to target certain glutamate receptors-called kainate receptors-that appear to play a role in the development of seizures.

In models, Mott is focusing on the hippocampus, the part of the brain that governs learning and memory and is the most common site of seizure activity.

"We're still several years away from a human trial, but we've developed a modified virus that does what it's supposed to do in the models. We're hopeful that targeting these receptors will stop seizures," Mott said.


The chemistry of anxiety 

Anxiety disorders such as panic attacks and post-traumatic stress disorder often involve an imbalance of brain chemicals, which often is corrected with precise dosages of medication.

Marlene Wilson is exploring another approach that could be used to treat anxiety or depression, which sometimes won't respond to medication.

"We were one of the first groups to look at how specific proteins affect anxiety and identify brain circuits that are responsible for stress disorders."

"My lab is using selected virus vectors that target certain cell types in the brain," she said. "We were one of the first groups to look at how specific proteins affect anxiety and identify brain circuits that are responsible for stress disorders. We think receptors in the brain's endogenous opioid system play a role in disorders such as social phobias and generalized anxiety."

Studies suggest that people and animals with high levels of a certain brain protein -- called neuropeptide Y -- can cope better with stress, appearing less anxious, less emotional, and more resilient to traumatic events.

"We're interested not only in the role of this peptide in anxiety disorders but also in knowing its relationship to alcohol because there appears to be a strong relationship between anxiety disorders and alcohol abuse," Wilson said.

Diabetes-related disorders

Scientists have long understood the biochemistry of insulin deficiency and diabetes, but the effects of insulin on the central nervous system are far less understood.

Larry Reagan is using a modified virus as a tool to study those effects and the larger relationship between diabetes and development of other neurological disorders.

"Depressive illnesses and Alzheimer's disease are just a couple of the comorbidities associated with diabetes," Reagan said. "Using our specialized virus, we're looking at how decreasing insulin receptors in the brain affects the structure and function of neurons.

"We already know that with fewer insulin receptors, you start to see indications of accelerated brain aging. Diabetics' brains appear to be older, which is perhaps why they develop age-related diseases such as Alzheimer's."

Could boosting insulin receptors in the brain have a positive effect? "One of the newest things from a clinical perspective is administering insulin intranasally to increase cognitive function in Alzheimer's patients," Reagan said. "No one really knows how the insulin has that effect on the brain -- that's the big unknown, and that's why we're using the virus to try to map it out."

Posted: 11/11/09 @ 12:00 AM | Updated: 08/09/11 @ 9:12 AM | Permalink