Epilepsy is a brain disorder that causes recurring, unprovoked seizures. It is the fourth most common neurological disorder worldwide.
Seizures are caused by sudden surges of abnormal and excessive electrical activity within networks of neurons in the brain. They can affect how a person appears or acts.
Epilepsy may arise due to genetic abnormalities, brain injury, or other unknown “cryptogenic” causes. The International League Against Epilepsy (ILAE), the world’s pre-eminent association of doctors, health professionals and scientists working in the field of epilepsy, defines the disorder based on the occurrence of any one of the following 1:
- At least two unprovoked (or reflex) seizures occurring >24 h apart;
- One unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years;
- Diagnosis of an epilepsy syndrome.
At Autifony, we are currently focused on the Progressive Myoclonic Epilepsies (PMEs).
These are rare syndromes that often have genetic abnormalities as the root cause. PME is characterised by:
- Myoclonic seizures i.e. muscle twitches or jerking movements
- Ataxia i.e. lack of voluntary coordination of muscle movement
PMEs are currently poorly treated, with the available anticonvulsant drugs ineffective against myoclonic seizures or the progressive ataxia. By targeting the underlying pathophysiology, Autifony’s Kv3 positive modulators have the potential to treat both myoclonus and ataxia in these patients. Initial clinical trials will explore efficacy in a form of PME caused by a loss-of-function mutation in the Kv3.1 (KCNC1) gene: “Myoclonic Epilepsy and Ataxia due to KCN1 mutation” (MEAK), also known as “EPM7”. “MEAK” or “EPM7” is very rare, occurring in just 1 in 5,700,000 conceptions 2.
Patients with MEAK have a reduced function of their Kv3.1 channels which gives rise to myoclonic seizures and ataxia.
Symptoms emerge between the ages of 3 and 15, with progressively severe myoclonus, ataxia, and occasional tonic-clonic seizures. Patients are typically wheel-chair bound by the time they are in their late teens.
Although current anti-epileptic drugs can help to reduce the incidence of tonic-clonic seizures, these drugs do not improve the myoclonus or ataxia.
MEAK shows many similarities to another PME syndrome, Unverricht-Lundborg syndrome 3, and research suggests that they have common final pathophysiology relating to reduced function of parvalbumin-positive interneurons.
The ILAE has recently highlighted the need to target the pathophysiology that may be common across epilepsy syndromes irrespective of underlying cause. The similarities between MEAK and Unverricht-Lundborg syndromes are one example of this; other related disorders could include other PMEs and broader diagnoses such as some forms of Juvenile Myoclonic Epilepsy (JME) and Temporal Lobe Epilepsy (TLE).
AUT00201 clinical candidate – designed to fulfil an unmet medical need for the treatment of Progressive Myoclonic Epilepsy
There are currently no drugs available specifically for the treatment of PMEs; existing anti-epileptic drugs help to reduce the incidence of tonic-clonic seizures but do nothing to improve the predominant symptoms of myoclonus or ataxia.
Patients with MEAK have one mutated copy of the KCNC1 gene and one normal copy, thus they produce Kv3.1 channels that are a mixture of the two. These “heteromeric” channels are less active than normal Kv3.1 channels so the amount of potassium current in neurons that express Kv3.1 channels is reduced. The reduced firing of these neurons in different brain areas gives rise to myoclonic seizure and ataxia.
Autifony has worked with researchers at the Children’s Hospital of Philadelphia and Jefferson University to demonstrate that AUT00201 can:
- Restore Kv3.1 channel function in cell lines expressing the mutated channels,
- Improve the firing of neurons in the brains of mouse models that express the mutant channels in vitro, and
- Completely reverse the seizure sensitivity and ataxia of these mouse models in vivo.
Based on these results, Autifony is now progressing AUT00201 into a Phase 1b proof-of-mechanism clinical trial in patients with MEAK.
- Fisher et al. 2014. Epilepsia. 55: 475-482
- Muona et al. 2015. Nature Genetics. 47: 30-46
- Oliver et al. 2017. Annals of Neurology. 81:677-89