Trends in Neurosciences
ReviewCell and gene therapies in epilepsy – promising avenues or blind alleys?
Introduction
The majority of patients with epilepsy suffer from focal (partial) seizures, which begin in one part of the brain and then spread. Temporal lobe epilepsy (TLE), the most common and difficult to treat type of partial epilepsy (Box 1), is typically associated with pathological alterations in the hippocampus and parahippocampal regions that are thought to be causally involved in the processes leading to the clinical symptoms of epilepsy and its comorbidities 1, 2 (Figure 1). Pathological changes in the hippocampus of patients with TLE are multiple and relate to structural and cellular reorganization of hippocampal formation, selective neurodegeneration and acquired changes of expression, distribution and function of neuroactive molecules, neurotransmitter receptors and ion channels underlying modified neuronal excitability 1, 2, but involve also alterations in glial function [3], mitochondria [4] and the blood–brain barrier 5, 6. Models of TLE (Box 2) are either based on kindling of limbic structures such as the amygdala or hippocampus or a result of experience of a prolonged status epilepticus (SE) induced by kainic acid, pilocarpine or sustained electrical stimulation which lead, after a latency period, to the expression of spontaneous seizures. Based on experiments in such animal models of TLE and clinical studies, an initial brain-damaging insult is thought to trigger a cascade of neurobiological events during the latency period (corresponding to epileptogenesis), which leads to the occurrence of spontaneous seizures and to the diagnosis of epilepsy (Figure 1). Innovative treatments may either be targeted to epileptogenesis, the morphological and functional changes leading to epilepsy after an initial brain insult, or to ictogenesis, the processes involved in initiation, propagation and amplification of seizures in the epileptic brain (Figure 1). Based on this concept and the limitations of conventional therapies (Box 1), partial epilepsy such as TLE is a potential target for both cell transplantation and gene therapy. These treatments can be used to directly target seizure foci or seizure propagation pathways, which is not possible by systemic administration of antiepileptic drugs (AEDs). The topic of cell and gene therapies for epilepsy has recently been covered in several excellent review articles 7, 8, 9, 10, 11, and several aspects of this topic are described in much greater detail in these recent reviews. In the present review, we will primarily focus on the antiepileptogenic, anticonvulsant and disease-modifying potential of such therapies (Figure 1), whereas readers interested in the use of cell or gene therapies for neuroprotection or structural repair in epilepsy are referred to previous reviews dealing with this important aspect 9, 12.
Section snippets
Transplantation of fetal cells as a potential therapy for epilepsy
Neural transplantation has traditionally been considered in the context of neurodegenerative disorders of the basal ganglia, such as Parkinson's disease (PD) and Huntington's disease, which are characterized pathologically by relatively selective cell loss in the basal ganglia, so that cell replacement through transplantation seems logical 13, 14. Initial studies with transplantation of rat fetal neural tissue to the adult rat brain were performed some 30 years ago by Björklund and colleagues,
Transplantation of genetically engineered cells (ex vivo gene transfer) as a potential therapy for epilepsy
Gene therapy fundamentally involves the transfer of genetic material to a cell and subsequent expression of the gene product [36]. There are two main approaches for gene therapy in the brain, ex vivo and in vivo gene transfer. The ex vivo approach involves genetically engineering cells ex vivo to express the desired ‘therapeutic’ gene and then implanting the cells into the target tissue. Experiments using this ex vivo approach in rat models of TLE are summarized in Table 2 and discussed in the
In vivo gene transfer as a potential therapy for epilepsy
The in vivo approach of gene therapy uses recombinant viral vectors, where the gene of interest is transferred to the infected cell, followed by expression of the gene product. This approach has great value in identifying potential cellular alterations as relevant to epileptogenesis and is thus an important research tool. Compared to the ex vivo approach, which is limited by restricted viability of cells, in vivo gene transfer promotes long-term expression of the related proteins [8]. Several
Concluding remarks
Numerous studies now have demonstrated that cell and gene therapies in acute and chronic models of epilepsy result in anticonvulsant effects, might be antiepileptogenic and might afford neuroprotection or neural repair. However, before moving from preclinical research to the clinical arena, several concerns have to be addressed. Although substantial seizure suppression can be obtained with cell grafting, the anticonvulsant effect was restricted to a few weeks in most rodent studies in which
Acknowledgements
We thank Thomas J. McCown and Steven C. Schachter for providing information on some aspects of this review and Annamaria Vezzani for critical comments on an earlier draft of the manuscript. The authors’ own studies were supported by grants from the Deutsche Forschungsgemeinschaft (Bonn, Germany). The authors declare that they have no competing financial interests.
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