Base editing boosts KCNQ2 protein in cultured cells

A regulatory sequence in the KCNQ2 gene has been inactivated—but only in cultured cells so far. Researchers at Northwestern Medicine used DNA base editing to inactivate a regulatory sequence and found that cells produced more functional KCNQ2 potassium-channel protein, a result that could support a future treatment strategy for a severe genetic form of epilepsy.

KCNQ2 normally acts as a brake on the nervous system. The gene codes for a potassium channel that helps stop neurons from firing too much. Harmful KCNQ2 variants can disrupt that braking system, causing seizures during the first few days of life and contributing to impaired brain development, developmental delays and poor long-term neurological outcomes.

The team, led by Alfred L. George, Jr., examined human and mouse brain RNA datasets using bioinformatic and experimental methods. They identified an upstream open reading frame, or uORF, a potential protein-coding region that sits before the gene’s main code in messenger RNA. When a ribosome—the cell’s protein-making machinery—starts at that alternate site, it can stall there and reduce production of the main KCNQ2 protein.

Inactivating the uORF in cultured cells increased KCNQ2 protein synthesis and boosted potassium-channel activity. The source also reports that inactivating the uORF decreased KCNQ2 mRNA levels. George’s team says the added protein was functional, not merely more abundant. The researchers are now testing whether the effect holds in mice with pathogenic KCNQ2 variants; the published work does not yet show a benefit in animals or humans.

So what changes in practice? The result is not a treatment for patients today. If the mouse experiments reproduce the cell results, the approach could provide a proof of concept for a potentially permanent disease-modifying gene therapy, while its safety and clinical benefit would still need to be established.