Ion Channels as Anti-Epileptic Drug Targets
Ion channels are pore-forming protein complexes that allow for the transport of charged ‘ions’ across the cell membrane. The flow of ions through these channels results in the production of an electrical signal. Ion channel signalling is crucial for regulating numerous vital functions throughout the human body, including cardiac function (heart contraction and rhythm) and neuronal signalling in the brain and spinal cord (coordinating sensation, behaviour, and emotion).
In excitable cells, such as neurons in the brain, ion channels permit electric signals to travel across the surface of the cell in a ‘wave’ of electrical impulses known as ‘action potentials’. Action potentials are propagated via a concert of rapid ion channel activity and can travel the length of a human nerve cell (up to 1 metre) in a matter of milliseconds! This phenomenon was first described in 1952 by Nobel Prize winners, Hodgkin and Huxley, where they directly measured action potential propagation in the ‘giant squid axon’ preparation. In these classical experiments, ‘axons’ (long neuronal projections similar to electrical cabling) were dissected from the squid, owing to its large size, allowing electrical impulses to be more easily studied.
The human brain is composed of vast networks of neurons, with their axons forming long projections, totalling approximately 100 kilometres in length. These axons allow for rapid transfer of information in our very own fibre-optic style network. Underlying the activity of these neuronal networks are ion channels, who’s role is to regulate sending and receiving of information and to maintain an equilibrium of neuronal activity.
How does epilepsy occur?
In many neurological disorders, such as epilepsy, there is an imbalance in the level of neuronal activity in the brain. This is commonly due to inherited genetic mutations in the DNA sequences of ion channels, resulting in irregular ion channel activity. Consequently, epileptic patients experience an abnormally high level of brain activity, resulting in the onset of debilitating seizures.
Thus, to alleviate these symptoms, ion channels have been a major focus of drug discovery in an attempt to restore the balance of activity in the brain. Various ways of targeting these channels are being explored.
Small-molecule drugs
Due to their size, small-molecule drugs are generally well-absorbed by the human body and thus are a popular approach for drug discovery projects. The chemical properties of small-molecule drugs are also readily modifiable and can be tailor-made to bind to the drug target of choice.
Considerable research is currently ongoing into the identification and development of small-molecule ion channel modulators which can reduce seizure activity. One approach that has shown promise is to develop drugs that work by selectively binding mutant ion channels to restore their regular function. A number of pharmaceutical companies are active in this area, and lead candidates are now progressing into human clinical trials.
Antisense oligonucleotides (ASOs)
Despite the relative success of small-molecule drugs for the treatment of epilepsy, these drugs can result in adverse effects due to ‘off-target’ effects in the human body. Thus, some companies are seeking to develop more precise targeting strategies.
One approach that is currently being developed involves the precision targeting of ion channels containing common epilepsy mutations, using antisense oligonucleotides (ASOs). ASOs are short single-stranded RNA molecules capable of ‘silencing’ specific genes. By targeting the defective gene directly, the faulty ion channel can be accurately ‘switched off’, regaining a balance of electrical activity in the brain and reducing epileptic seizures.
ASOs tackle the root cause of epilepsy symptoms with high precision, reducing potential adverse effects that may occur with classical small-molecule drugs. ASO pharmacology shows great promise as a potential new class of anti-epileptic drugs.
Stem cell therapy
For patients that do not respond to small-molecule anti-epileptic drugs, further alternative approaches are being explored.
Stem cells are ‘un-programmed’ cells which can be specialised for specific functions. In a recent study, stem cells were ‘programmed’ as inhibitory neurons and injected directly into the brain of patients suffering from severe epilepsy. This type of neuron dampens electrical activity in the brain, through inhibitory ion channel activity. Incredibly, the two epilepsy patients participating in this US clinical trial displayed almost complete abolition of seizures following treatment. This stem cell therapy may offer a much-needed alternative approach for epilepsy treatment.
In summary, there are therefore a number of exciting anti-epileptic approaches being explored and it will be interesting to see how the field develops over time.
J A Kemp has extensive expertise in protecting innovations in a wide range of medical technologies, including in Pharmaceuticals, RNA/Oligonucleotide technology and Cell and Gene Therapy.