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Robert Stephens, PhD, & Brian Kaspar, PhD

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Viral-mediated spinal glutamate transporter over-expression and visceral pain

StephensThe OSU CCTS has awarded Robert Stephens, PhD, and Brian Kaspar, PhD, a one-year pilot grant for their research study, “Viral-mediated spinal glutamate transporter over-expression and visceral pain.

Kaspar has been at Nationwide Children’s Hospital for six years. Previously, his post-doctoral studies at the Salk Institute focused on gene delivery to the central nervous system.

“What has really plagued the ability for drugs or therapies getting to the brain or spinal cord is the blood-brain barrier,” Kaspar said. The blood-brain barrier is a selectively permeable layer of tightly-packed cells that serves to protect the central nervous system.

KasparThe blood-brain barrier offers many benefits. It protects the brain from foreign substances in the blood, shields the brain from hormones and neurotransmitters in the body, and enables the brain to maintain a constant environment. The downside of the barrier is that the central nervous system is not easily accessible when a problem involving a neurodegenerative or pain disease occurs.

But at the end of 2009, Kaspar and his team discovered a virus capable of penetrating the blood-brain barrier. The virus, called the adeno-associated virus 9 (AAV-9), was not only capable of transcending the barrier, but also targeted cells within the brain and spinal cord when placed into neonatal and adult animals.

“Many people had been searching for drugs or therapies or ‘Trojan horses’ to sneak by the blood brain barrier, and we were one of those groups,” Kaspar said. “There are hundreds of these AAVs—some do better at targeting [different organs] and most do not make it past the blood brain barrier.”

For reasons the team does not yet fully understand, AAV-9 makes its way past the barrier.

“This really was the first finding of efficient and robust delivery of a gene into the brain,” Kaspar said. “That’s how our lab is focused, on the development of novel approaches and technologies to deliver efficiently to the brain or spinal cord when something goes wrong.”

Separately, Kaspar and Stephens had been working with the same gene, called excitatory amino acid transporter type-2 (EAAT-2). Kaspar was interested in the gene’s role in amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, while Stephens was applying it to the context of pain.

Kaspar and Stephens were familiar with each other’s work and decided to collaborate on their research. They submitted a pilot project to the CCTS that involved trying to deliver the EAAT-2 gene in models of pain to see if the pain could be eliminated. Past treatment options for such pain have involved drilling a hole in the brain and inserting a needle into the brain or spinal cord to deliver a drug or therapy.

Studies performed by Stephens showed that an over-expression of EAAT-2 allowed for better modulation of pain than a lack of EAAT-2. In their pre-clinical studies, the team has found that motor neurons and dorsal root ganglia neurons, which are receptive towards the pain pathway, were efficiently targeted.

Kaspar said the overarching goal of the study is to deliver EAAT-2 into the region where pain is caused. Once there, it will “suck up and transport” excess glutamate, which has been linked to disease and pain, thereby reducing visceral (organ) pain.

Kaspar and Stephens hope to have their preclinical efficacy data, and possibly even more data, within the next six months.

“Ultimately, if successful, this could turn into a product that could treat pain that is [untreatable] with other sorts of commonly prescribed drugs or therapies,” Kaspar said. “This is opening up a door to certain types of pain that are resistant towards other or more common therapies.”

By Nicole Frie, Friday, August 20, 2010

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