Novel Adeno-associated viral vector (AAV) mediated RNA editing treatment for KCNT1 epilepsy

Awardee: Rajvinder Karda

Institution: University College London

Grant Amount: $70,619.00

Funding Period: February 1, 2024 - January 31, 2025

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Summary:

KCNT1 epilepsy is a severe childhood genetic epilepsy, which leads to life-long disability. Spelling mistakes, or mutations, in the genetic code of KCNT1 cause epilepsy of infancy with migrating focal seizures (EIMFS). EIMFS becomes apparent in the first 6 months of life, where babies present with frequent seizures, developmental delay, and movement disorders. Sadly, patients also have an increased chance of premature death. The KCNT1 gene codes for a potassium channel which changes nerve cell (neuron) excitability. Mutations associated with this form of epilepsy result in increased channel activity in brain cells, making them more excitable. Current drug treatments are unfortunately inadequate and ineffective. The process of making proteins in cells involves translating DNA (the genetic code) into RNA (the protein code) which is then made into proteins such as the KCNT1 channel. We aim to develop a novel RNA editing therapy treatment for EIMFS, altering the protein code so less protein is made. We will deliver the RNA treatment within a virus called adeno-associated virus (AAV). When the AAV enters neurons, it will reduce the amount of KCNT1 protein and normalise the channel activity. We will test this new treatment in a Kcnt1 mouse model which has an over-active KCNT1 channel and seizures very similar to those seen in patients. We will also test the treatment in neurons made from skin cells donated by patients with KCNT1 epilepsy. In the future we hope this could be developed into a treatment for patients. Although like other gene therapies it would need to be delivered to the brain, our treatment would have several advantages including being a one-off treatment unlike other RNA treatments which require repeated spinal taps or lumbar punctures. Therefore, in this proof-of-concept study we will develop and test a novel RNA editing one-off treatment to improve KCNT1-epilepsy.