In earlier studies, McCown and his team learned there would be no attenuation of seizure activity if galanin was produced within neurons and wasn't secreted from the cells. In addition, brain cells would die following induced seizures. Moreover, these cells were in a brain area intimately involved in temporal lobe epilepsy, McCown said.
In the new research, the cargo delivered via AAV included coded instructions for galanin and a secretory sequence that caused the galanin to be non-specifically secreted from the cell. In one experiment, sensitivity to focal seizure was reduced significantly. In another model seizure experiment, the AAV "construct" was delivered to only one side of the brain. Cell death after seizure induction occurred only in the untreated area.
"The treated side looked normal," McCown said. "This suggests that we can secrete an active peptide in a brain structure that's closely tied to temporal lobe seizures."
Gene expression following delivery the AAV construct can be turned off by the antibiotic doxycycline, which McCown said was an important feature of the research. "Whether it be via an antimicrobial compound or an analog, this is an absolutely crucial component to human gene therapy. You have to be able to turn gene expression off."
In terms of focal seizure control through gene therapy, the new study brings researchers a step closer to resolving a major issue: how to influence only a specific area of the brain. "In the case of seizures, the area is much more restrictive than that of a single-gene disorder where you need to hit most of the cells in a large proportion of the brain," McCown said.
Further laboratory studies with this new gene therapy platform may prove promising for treatment of temporal lobe epilepsy patients who are slated for surgery, McCown said. "You could put in this AAV vector prior to surgery and then see what effect it has on the tissue to be removed.
If it control
Contact: Leslie Lang
University of North Carolina School of Medicine