Gene therapy has delivered promising results in early stage clinical trials for other neurological disorders such as Parkinson's disease,[2] raising the hope that it will become a treatment for intractable epilepsy.
[5][6] For such patients, surgery to remove the epileptogenic zone can be offered in a small minority, but is not feasible if the seizures arise from brain areas that are essential for language, vision, movement or other functions.
[citation needed] Through the use of viral vector gene transfer, with the purpose of delivering DNA or RNA to the epileptogenic zone, several neuropeptides, ion channels and neurotransmitter receptors have shown potential as transgenes for epilepsy treatment.
As the seizures that characterize epilepsy typically result from excessive and synchronous discharges of excitatory neurons, the logical goal for gene therapy treatment is to reduce excitation or enhance inhibition.
Due to the decrease in these nucleosides that possess anti-epileptic properties and the overexpression of the ADK, seizures are triggered, potentially resulting in the development of epileptogenesis.
Through the use of mice that are deficient in GalR1 receptors, a picrotoxin-kindled model was utilized to show that galanin plays a role in modulating and preventing hilar cell loss as well as decreasing the duration of induced seizures.
The hope of gene therapy is that by overexpressing somatostatin in specific cells, and increasing the GABAergic tone, it is possible to restore balance between inhibition and excitation.
It is widely expressed in the brain and peripheral nerves, and plays a role in controlling the excitability of neurons and the amount of neurotransmitter released from axon terminals.
Gene therapy with a modified potassium channel delivered using either a non-integrating lentivector that avoids the risk of insertional mutagenesis or an AAV has also been shown to be effective in other models of epilepsy.
[17] A potential obstacle to clinical translation of gene therapy is that viral vector-mediated manipulation of the genetic make-up of neurons is irreversible.
Several laboratories have shown that the inhibitory light-sensitive protein Halorhodopsin can suppress seizure-like discharges in vitro as well as epileptic activity in vivo.
[22] AAV-mediated expression of hM4D(Gi) in a rodent model of focal epilepsy on its own had no effect, but when activated by the drug clozapine N-oxide it suppressed seizures.
[23] A 'closed-loop' variant of chemogenetics to stop seizures, which avoids the need for an exogenous ligand, relies on a glutamate-gated chloride channel which inhibits neurons whenever the extracellular concentration of the excitatory neurotransmitter glutamate rises.
[24] A mouse model of Dravet syndrome has been treated using a variant of CRISPR that relies on a guide RNA and a dead Cas9 (dCas9) protein to recruit transcriptional activators to the promoter region of the sodium channel gene Scn1a in interneurons.
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