Bridging the Gapmer: promising gene therapy for rare epilepsy
Targeting a gene variant associated with seizures could lead to a novel treatment for drug-resistant epilepsy.
In a recent study, a team of researchers from the Yong Loo Lin School of Medicine, National University of Singapore (Kent Ridge, Singapore) have utilized a specialized antisense oligonucleotide (ASOs) to develop a gene therapy targeting faulty mRNA coding for a subunit of potassium ion channels that cause epilepsy. The team observed remarkable results in in vitro cell samples and with further development, this therapy could offer hope for patients with rare forms of epilepsy or related gene mutations.
In 2021, the research team was approached by a family whose infant was subject to multiple generalized seizures, where standard treatments had been ineffective. The infant’s epilepsy gene panel revealed a missense mutation in KCNA2, which encodes the Kv1.2 proteins that form part of voltage-gated potassium channels responsible for regulating electrical signals in the brain. The infant also exhibited developmental delays, speech difficulties and ataxia, aligning with KCNA2-related infantile epileptic encephalopathy, a condition that affects brain function.
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Mutations in the KCNA2 gene can cause potassium channels in the brain to malfunction. Hua Huang, who led the study, explained that, “Epilepsy is associated with hyper-excitable neurons and potassium helps dampen the excitability levels. The potassium channel encoded by KCNA2 is like a door that controls the potassium ion flow on the surface of the cells – when the gene is mutated, the door fails to work and potassium cannot be released to control neuron activity, which results in epilepsy.”
In their efforts to find a treatment for the patient, the researchers created both normal and mutated versions of the gene that codes for a constituent subunit of a voltage-gated potassium channel. They discovered that the mutated protein not only failed to function on its own but also disrupted the activity of the normal protein, reducing potassium channel activity. Given the complex structure of potassium channels, the researchers realized that designing a single small-molecule drug to address all the possible combinations of the channels caused by the KCNA2 mutation would be difficult. Therefore, they opted for a different approach.
The researchers utilized Gapmer ASOs to specifically target and silence the mutated mRNA while preserving the normal mRNA. In early experiments, Gapmer antisense oligonucleotides bound more effectively to the mutated mRNA, reducing levels of the faulty protein without affecting the normal protein. This approach improved potassium channel function in cells expressing both normal and mutated proteins and appeared to lower the risk of seizures, showing promise as a potential therapy for addressing the KCNA2 mutation.
Although the research is still in its early stages and requires further testing in laboratory models before moving to clinical trials, the researchers are optimistic that this therapy could be available for patients with epilepsy caused by genetic abnormalities in ion channels within the next 10 to 20 years. “Since the therapy has shown promise in targeting a specific gene mutation causing epilepsy, [they] hope to eventually pioneer new treatment options for patients suffering from this condition and other similar gene mutations,” according to co-author Soong Tuck Wah.
