Transplants of Cells Engineered to Produce GABA Suppress Spontaneous Seizures

Abstract

Purpose: Cell transplantation into the brain is an aggressive clinical alternative. The hopes of treating diseases like intractable temporal lobe epilepsy have been subdued because the preclinical successes thus far have shown only slowing of epileptogenesis, or suppression of electrically induced seizures. Because the hallmark of epilepsy is spontaneous seizures, the clinical relevance of these studies has been questioned. The purpose of this study was to establish that cells genetically engineered to produce γ-aminobutyric acid (GABA) could suppress spontaneous seizures in an accepted model of temporal lobe epilepsy. Methods: Conditionally immortalized neurons were engineered to produce GABA under the control of tetracycline. These cells were transplanted into the substantia nigra of spontaneously seizing animals. After transplantation, the animals were monitored for 3 days immediately after surgery and again for 3 days beginning 7-8 days after surgery. Seizures and epileptiform spikes were recorded and later analyzed with detection software combined with video monitoring. Results: Animals that received genetically engineered GABA-producing cells had significantly fewer spontaneous seizures than did animals that received control cells, or animals that received GABA-producing cells plus doxycycline at the observation period starting 1 week after transplantation. A significant suppression of epileptiform spikes also was noted between the group that received GABA-producing cells and the group that received the same cells but were given doxycycline. The engineered cells show evidence of integration with the host but limited survival. Conclusions: These data demonstrate that genetically engineered cells have the ability to suppress spontaneous seizures when transplanted into seizure-modulating nuclei. This is an important step toward defining a clinical potential for this approach in epilepsy. The fact that the gene of interest can be regulated suggests that individualizing transplant therapy may be possible.