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Engineered Cells Identify Rare Epilepsy Drug Candidates

Genetic testing illustration

(National Institute of General Medical Sciences, NIH)

4 December 2017. A process using high-speed screening of drug candidates with genetically engineered cells identified potential drugs to treat a rare form of childhood epilepsy. A team from the start-up company Pairnomix LLC in Plymouth, Minnesota and the KCNQ2 Cure Alliance are presenting their findings at the annual meeting of the American Epilepsy Society now underway in Washington, D.C.

Pairnomix, which began in January 2016, offers personalized genetic testing to find treatments for rare disorders. The company says it creates a lab model of genomic mutations responsible for rare diseases by genetically engineering healthy DNA to simulate the mutation, then inserting the mutated DNA into cells. There the cells are tested for functions similar to cells with the rare disease. The cells with mutated DNA are used to screen some 1,300 approved drugs for activity against the rare disease, highlighting and confirming the top candidates.

When Pairnormix got underway, it began a joint project with the KCNQ2 Cure Alliance in Denver to find potential treatments for KCNQ2 epileptic encephalopathy, or KCNQ2E, a rare form of epilepsy. The disorder results from a mutation in the KCNQ2 gene responsible for proteins that make potassium channels for sending and receiving signals from cells. These proteins and channels are particularly important in nerve cells, where they regulate electrical signals in the brain, keeping the nerve cells from becoming overactive or excitable.

KCNQ2E is believed to affect some 500 individuals worldwide, mainly infants that exhibit seizures in their first weeks of life. KCNQ2 Cure Alliance says the seizures often resolve themselves as children get older, but they can leave children with mild to severe impaired development, including symptoms similar to autism. The low numbers of reported cases, says Pairnormix, may be due to the relatively recent discovery of the disorder as well as the need for genetic testing to detect it.

In the conference paper, the team led by David Goldstein — geneticist and neurology professor at Columbia University, and scientific board member at Pairnormix — added mutated KCNQ2 genes to standard lab cell lines to generate signaling patterns similar to those found in KCNQ2E. These cells with mutated genes and comparable cells with normal genes were then used to screen a library of 1,280 known off-patent drugs, as well as known epilepsy drugs and compounds that act against the signaling channels affected by the mutations.

The screening identified 60 drugs that act against signals from the mutated cells. Among the more active drugs found through this process is paroxetine, an anti-depressant also prescribed for bipolar disorder and other neurological conditions. The team says many of the drugs highlighted through the screening were not previously associated with signaling patterns like those found in KCNQ2E. The researchers conclude that the screening process with genetically-modified cells can be useful in identifying treatments for rare disorders among currently available drugs developed for other, even unrelated, conditions.

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