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ment in individuals with TSC 44-47. In Chapters 5 and 6, we describe that miRNAs 21, 146a, 147b and 155 were increased expressed in cortical tubers. In addition, these miRNAs were upregulated under inflammatory conditions mimicked by IL-1β signaling, both in human astrocyte cultures and in cell cultures derived from surgically resected brain tissue from patients with TSC. We identified that miR146a and miR147b were potent negative regula- tors of inflammatory signaling, and that they could also inhibit other hallmarks of gliosis like aberrant astrocytic proliferation and differentiation from the neuronal precursor cell pool. Summarizing, we pinpointed some miRNAs with therapeutic potential in epi- leptic pathology in TSC, although their therapeutic role in epilepsy should be further investigated. Recently, it has been reported that administration of miR146a in the brain reduced seizures and prevented disease progression in a rodent model of epilepsy 48. Also other studies suggested that miRNAs related to neuroinflammation (e.g. inhibition of miR34a, miR132, miR134 and miR155 and overexpression of miR22, miR124 and miR128) could be used as therapeutic strategy in epilepsy 49-51. Currently, functional studies should validate the therapeutic potential of miRNAs that are reported to be involved in disease pathogenesis in epilepsy 52. This includes an expansion of studies with higher clinical rel- evance, e.g. where the experimental set-up includes administration of miRNAs or inhib- itors after disease onset. Also, it should be clear through which cell type the miRNAs or anti-miRNAs exert their effects, since most approaches lack cell specificity. Preferably, therapeutic approaches should be established that not only suppress seizures during use (anti-ictogenic), but also have disease modifying effects (anti-epileptogenic) and would therefore only need transient administration. Furthermore, where functional studies in cell cultures use transfection methods for overexpression of knockdown of miRNAs and compounds in animal models are often administered via intracerebral injec- tion, administration routes for use in human clinic yet have to be established. So far, multiple clinical trials have been initiated using miRNA- and small interfering RNA (siR- NA)-based compounds, of which some already entered phase II clinical trials 53. Many miRNAs are ubiquitously expressed throughout the body, therefore a brain-specific or even region-specific delivery of miRNA-based therapies for the treatment of epilepsy is necessary. Unfortunately, miRNA-based therapeutic compounds are unable to cross the intestinal membrane or the intact blood-brain-barrier which eliminates the possibility of oral administration. One invasive yet CNS specific oligonucleotide delivery has been described via intrathecally lumbar puncture of nusinersen 54. Nusinersen is an antisense oligonucleotide-based compound developed for the treatment of spinal muscular atro- phy, and phase II and III trials show good outcome 55-57. Intrathecally lumbar puncture might therefore be a potential alternative choice of treatment for surgery if regular med- ical treatment fails 54, 56, 58. However, a less invasive method of administration is preferred, and currently studies are performed investigating the feasibility of intranasal delivery of miRNAs 51. Other in vivo delivery systems include the use of locked nucleic acid anti- miRs, or miRNA delivery using neutral lipid emulsions, viral vectors, lipid nanoparticles, liposomes or coupling to other carries molecules 59. Key challenges that have to be over- come in miRNA-based treatments include adverse inflammatory side effects, toxicity due to charge of the compound, targeting to the disease site and endosomal degrada- tion of oligonucleotides by RNAses after internalization into the target cell 59. The major- ity of the current studies are testing the applicability of intravenous injection of miRNAs