A New Approach for Treating Epilepsy
Epilepsy is a brain disorder in which sudden changes in the brain’s electrical activity cause recurrent seizures, which in turn manifest as involuntary changes in movement, sensation, or consciousness. For instance, seizures may range from a few muscle jerks to severe convulsions. While drug, diet, and surgery options exist for treating epilepsy, their use depends on restrictive criteria; for example, the diet treatment is mainly effective in children with a specific type of epilepsy. Similarly, surgery is only considered for specific types of epilepsy and would not result in major complications. As for drug options, 30% of epilepsy patients are resistant to current antiepileptic medications.
Researchers at University College London aimed to overcome this issue through gene therapy that selectively targets the neurons responsible for triggering epilepsy, therefore mitigating any resulting side effects. In their study, they used a viral vector gene therapy, or a virus genetically engineered to insert therapeutic genes of interest into cells. Viral gene therapies cannot distinguish epileptic from non-epileptic neurons, and so would insert DNA into both types.
However, the researchers’ solution to this problem was having their therapeutic vector include an activity-dependent promoter, or a type of promoter (sequence of DNA that induces expression of a gene downward from it) that is rapidly responsive to increases in neuron activity. The induced gene will code for protein Kv1.1, which lowers neuronal activity. Therefore, this solution is selective in that the promoter will only induce expression of the Kv1.1 protein in situations of rapid increases of neural activity, which takes place only in epileptic neurons, and will switch off once the seizure is over. So, the gene therapy would not activate in non-epileptic neurons even if present in them, additionally preventing possible side effects.
Researchers at University College London aimed to overcome this issue through gene therapy that selectively targets the neurons responsible for triggering epilepsy, therefore mitigating any resulting side effects. In their study, they used a viral vector gene therapy, or a virus genetically engineered to insert therapeutic genes of interest into cells. Viral gene therapies cannot distinguish epileptic from non-epileptic neurons, and so would insert DNA into both types.
However, the researchers’ solution to this problem was having their therapeutic vector include an activity-dependent promoter, or a type of promoter (sequence of DNA that induces expression of a gene downward from it) that is rapidly responsive to increases in neuron activity. The induced gene will code for protein Kv1.1, which lowers neuronal activity. Therefore, this solution is selective in that the promoter will only induce expression of the Kv1.1 protein in situations of rapid increases of neural activity, which takes place only in epileptic neurons, and will switch off once the seizure is over. So, the gene therapy would not activate in non-epileptic neurons even if present in them, additionally preventing possible side effects.
Mice models are used for in vivo studies since they may more accurately model a clinical condition than in vitro studies, which use cells in a dish. Thus, they would help test the safety and efficacy of this gene therapy approach for epilepsy.
Image Source: Shutterbug75
The researchers first demonstrated the responsiveness of the activity-dependent promoter c-Fos in in vitro mouse neural cells. They started out with testing expression of GFP, a green fluorescent protein, under control of c-Fos as a simple readout of how effective c-Fos worked. Indeed, GFP expression increased upon artificial simulation of epilepsy in the in vitro cell cultures, indicating responsiveness of c-Fos. Next, they verified c-Fos-controlled Kv1.1’s ability to lower epileptic neural activity in an activity-dependent manner. They performed similar experiments in human neurons derived from induced pluripotent stem cells and observed similar results.
The researchers also performed in vivo mouse studies, which would be relevant in terms of clinical application. They virally transduced mice with GFP or EKC under control of c-Fos promoter, then chemically induced a single generalized seizure and observed the resulting changes in neural activity. They found that the neurons in mice treated with cFos-EKC had significantly less neuronal activity. This treatment also protected against a second seizure chemically induced after the first seizure. Additionally, they discovered that the treatment does not dramatically alter normal behavior, which they measured through abilities of fear recall, motor movement from one place to another, memory, and smell discrimination.
Finally, the researchers used a different type of mouse model that is drug-resistant to epilepsy and experiences seizures randomly. This kind of mouse model can be useful in situations where epilepsy is long-term and unpredictable, unlike the previous model before where they were able to control when to induce a seizure. Here, they observed similar results, in which mice treated with cFOS-EKC experienced less seizures.
These results are an example of how epilepsy resistant to current drugs or inaccessible to other therapeutic options may be treated. This approach may be able to be generalized to other diseases whose origin in some ways stem from overactive neurons, such as schizophrenia or Parkinson’s disease. Nevertheless, additional in vitro and in vivo experiments will need to be done to further characterize the safety and efficacy of this treatment in multiple forms of epilepsy as well as these other conditions.
The researchers also performed in vivo mouse studies, which would be relevant in terms of clinical application. They virally transduced mice with GFP or EKC under control of c-Fos promoter, then chemically induced a single generalized seizure and observed the resulting changes in neural activity. They found that the neurons in mice treated with cFos-EKC had significantly less neuronal activity. This treatment also protected against a second seizure chemically induced after the first seizure. Additionally, they discovered that the treatment does not dramatically alter normal behavior, which they measured through abilities of fear recall, motor movement from one place to another, memory, and smell discrimination.
Finally, the researchers used a different type of mouse model that is drug-resistant to epilepsy and experiences seizures randomly. This kind of mouse model can be useful in situations where epilepsy is long-term and unpredictable, unlike the previous model before where they were able to control when to induce a seizure. Here, they observed similar results, in which mice treated with cFOS-EKC experienced less seizures.
These results are an example of how epilepsy resistant to current drugs or inaccessible to other therapeutic options may be treated. This approach may be able to be generalized to other diseases whose origin in some ways stem from overactive neurons, such as schizophrenia or Parkinson’s disease. Nevertheless, additional in vitro and in vivo experiments will need to be done to further characterize the safety and efficacy of this treatment in multiple forms of epilepsy as well as these other conditions.
Featured Image Source: GDJ
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