Epilepsy

The hallmark of epilepsy is the occurrence of usually unpredictable, spontaneous seizures in the brain. These seizures are an event with a particular focus in the CNS; the cause is not precisely understood. It is either a symptom of specific congenital diseases or acquired following injury to the brain from sclerosis, tumors, abscesses, strokes or gliosis. Focal epilepsies can often be controlled by drugs that favour inhibitory over excitatory neurotransmission. Seizure activity, however, persists in approximately 35% of the patients taking these anti-epileptic drugs (Devinsky 1999). Medically intractable epilepsy, in cases of an identifiable epileptic focus, may be treatable through lesion surgery. Even so, in a number of patients surgery fails to control the seizures, and many patients cannot be surgically helped because of the (often extremely high) risk of losing important brain functions such as speech and motor control. Among the various new treatment techniques under investigation (Rosenfeld 2002), neurotransplantation and gene transfer were recently proposed after breakthroughs in the treatment of epileptic animal models (Freeman 2000).

Cells engineered to release GABA, the major inhibitory transmitter, or adenosine, known to suppress seizure activity, have been applied successfully as anticonvulsant treatments in rats experiencing chronic seizures (Löscher et al. 1998; Gernert et al. 2002). GABA-releasing cells are conditionally immortalised neurons genetically modified to over-express the GABA-syn-thetising enzyme GAD under the control of tetracycline. These cells, when placed intraparenchymally in the brain of animals experiencing spontaneous seizures, brought about a reduction in the number of spontaneous seizures (Thompson and Suchomelova 2004; Thompson 2005). The adeno-sine-releasing cells were modified by the genetic inactivation of adenosine kinase or aminase enzymes that normally break down adenosine. Encapsulated in semi-permeable membranes (see above in the section on HD), these cells prevent kindling-induced epilepsy in rats when placed intracerebroven-tricularly (Huber et al. 2001; Guttinger et al. 2005a).

The first human pilot study of the implantation of GABA-producing cells was performed in epilepsy patients who failed to respond to conventional epilepsy medication, and who are candidates for the surgical removal of a portion of the brain in order to control seizures (D. Schomer et al.; communicated at the 58th Annual meeting of the American Epilepsy Society, New Orleans 2004). These cells were fetal porcine neurons and the study aimed primarily to look at cell survival, host reaction, and clinical side effects. An ability to control seizures was reported in two out of three patients in this unblinded study. However, during the subsequent epilepsy lesion surgery, no implanted tissue was detected. The study was stopped as a result of this and also because of the concern about safety of porcine xenografting (see below). Currently, fundamental research is moving towards the option of using (human) neural stem cells as they differentiate into GABAergic neurons (Chu et al. 2004) following brain implantation. Moreover, they can be genetically modified so that they release seizure-reducing molecules (Guttinger et al. 2005b).

If cell implants can have an anti-epileptic effect through the release of seizure-reducing compounds, direct genetic modification of the cells in or around the epileptic focus would be an obvious alternative. The generation of AAV and LV viral vectors, which are capable of stable transduction of neurons, is an example of this type of strategy. Indeed, animal studies showed that an overexpression of galanin (Haberman et al. 2003; Lin et al. 2003) and neuropeptide Y (NPY) (Richichi et al. 2004; Noe et al. 2005) revealed significant anticonvulsant and anti-epileptic effects. Phase I studies with AAV-NPY treatment in intractable epilepsy are reported to be on the way (Neurologix; http://www.neurologix.net, accessed on December 7th, 2006).

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Brain Blaster

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