The SCN1A gene is just too giant to suit into aconventional viral supply programs. Scientists overcame this hurdle with a pioneering “split-intein” mechanism, which is like two separate vans, delivering the gene in two items. Credit score: Allen Institute
In a groundbreaking development for households grappling with the challenges of Dravet syndrome, a uncommon and life-altering type of epilepsy, scientists have developed a brand new gene substitute remedy in mice that might result in simpler therapies in people.
The findings seem in Science Translational Medication. The brand new remedy, a collaboration between researchers on the Allen Institute and Seattle Kids’s Analysis Institute, alleviated signs and led to long-term restoration with out toxicity, uncomfortable side effects, and loss of life.
“People who take drugs for epilepsy often complain that the drugs are very impactful; they can slow down the seizures but it changes a lot about their brain,” mentioned Boaz Levi, Ph.D., affiliate investigator on the Allen Institute, who co-led the examine with Franck Kalume, Ph.D., an affiliate professor on the College of Washington and principal investigator at Seattle Kids’s Analysis Institute.
“Our goal is to be very precise, where we can deliver just the gene that’s missing and really target the circuit. Because of that, it can be much safer, more effective, and significantly reduce side effects,” mentioned Levi.
Dravet syndrome impacts round 1 in 15,700 youngsters, and most instances are brought on by mutations within the SCN1A gene. This gene performs a vital position within the mind’s capability to manage exercise via fast-spiking interneurons. With extreme seizures and developmental delays, this illness has lengthy left households and researchers determined for simpler therapies.
Boav Levi, Ph.D., (left) and John Mich, Ph.D., (proper) within the laboratory at Allen Institute. Credit score: Jenny Burns / Allen Institute.
This new remedy includes an modern two-step technique:
Precision gene supply: Utilizing specialised enhancers (quick stretches of DNA that act like switches to regulate when and the place a selected gene is turned on), scientists had been capable of goal particular cells which can be faulty in sufferers with Dravet syndrome.
Fixing the puzzle of gene measurement limits: Gene remedy is completed via AAV vectors. These are innocent viruses that may carry genes into cells. However the SCN1A gene is just too giant to suit into standard AAV vectors, so scientists overcame this hurdle through the use of a protein fusion mechanism (split-inteins: see diagram beneath), which splits the gene into two components in order that it may be carried into the cell and reassembled as soon as inside. Every half is delivered to the identical cell by a separate virus the place they fuse collectively to make the ultimate gene. That is like delivering a big piece of furnishings into your private home in two components as a result of it might probably’t match via the entrance door after which reassembling it as soon as the items are inside.
Handled mice on this examine confirmed exceptional enchancment. Seizures had been alleviated, restoration was long-lasting, and no opposed results had been noticed.
What’s subsequent? A promising path ahead
These outcomes not solely help the potential of AAV-mediated SCN1A gene substitute, but additionally highlight the crucial position of cell-specific therapies in combating genetic issues like Dravet syndrome.
“These are people who are going to have a severely impacted standard of living,” mentioned Levi. “We are hopeful this sort of therapy could have a huge impact for families, and that’s what’s exciting to me.”
Extra data:
John Okay. Mich et al, Interneuron-specific dual-AAV SCN1A gene substitute corrects epileptic phenotypes in mouse fashions of Dravet syndrome, Science Translational Medication (2025). DOI: 10.1126/scitranslmed.adn5603
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Allen Institute for Mind Science
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Breakthrough gene remedy alleviates Dravet syndrome signs in mice with out uncomfortable side effects (2025, March 19)
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