Gene therapy is being studied for some forms of epilepsy. It relies on viral or non-viral vectors to deliver DNA or RNA to target brain areas where seizures arise, in order to prevent the development of epilepsy or to reduce the frequency and/or severity of seizures. Gene therapy has delivered promising results in early stage clinical trials for other neurological disorders such as Parkinson's disease, raising the hope that it will become a treatment for intractable epilepsy.
Overview
Epilepsy refers to a group of chronic neurological disorders that are characterized by seizures, affecting over 50 million people, or 0.4–1% of the global population. There is a basic understanding of the pathophysiology of epilepsy, especially of forms characterized by the onset of seizures from a specific area of the brain (partial-onset epilepsy). Although most patients respond to medication, approximately 20%–30% do not improve with or fail to tolerate antiepileptic drugs. 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. As a result, many people with epilepsy are left without any treatment options to consider, and thus there is a strong need for the development of innovative methods for treating epilepsy.
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. Among vectors are adenovirus and adeno-associated virus vectors (AAV), which have the properties of high and efficient transduction, ease of production in high volumes, a wide range of hosts, and extended gene expression. Lentiviral vectors have also shown promise.
Clinical research
Among challenges to clinical translation of gene therapy are possible immune responses to the viral vectors and transgenes and the possibility of insertional mutagenesis, which can be detrimental to patient safety. Scaling up from the volume needed for animal trials to that needed for effective human transfection is an area of difficulty, although it has been overcome in other diseases. With its size of less than 20 nm, AAV in part addresses these problems, allowing for its passage through the extracellular space, leading to widespread transfection. Although lentivectors can integrate in the genome of the host this may not represent a risk for treatment of neurological diseases because adult neurons do not divide and so are less prone to insertional mutagenesis
Viral approaches in preclinical development
In finding a method for treating epilepsy, the pathophysiology of epilepsy is considered. 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. Out of the viral approaches, neuropeptide transgenes being researched are somatostatin, galanin, and neuropeptide Y (NPY). However, adenosine and gamma-aminobutyric acid (GABA) and GABA receptors are gaining more momentum as well. Other transgenes being studied are potassium channels and tools for on-demand suppression of excitability (optogenetics and chemogenetics).
Adenosine
Adenosine is an inhibitory nucleoside that doubles up as a neuromodulator, aiding in the modulation of brain function. It has anti-inflammatory properties, in addition to neuroprotective and anti-epileptic properties. The most prevalent theory is that upon brain injury there is an increased expression of the adenosine kinase (ADK). The increase in adenosine kinase results in an increased metabolic rate for adenosine nucleosides. 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. Studies have shown that ADK overexpression results from astrogliosis following a brain injury, which can lead to the development of epileptogenesis. While ADK overexpression leads to increased susceptibility to seizures, the effects can be counteracted and moderated by adenosine. Based on the properties afforded by adenosine in preventing seizures, in addition to its FDA approval in the treatment of other ailments such as tachycardia and chronic pain, adenosine is an ideal target for the development of anti-epileptic gene therapies.