A couple of decades after the discovery of systems that could selectively target DNA, we're starting to see the first therapies based on gene editing. One challenge these developments have faced is safety. While we can make them pretty specific to the gene we want edited, the human genome is very large, and even rare DNA sequences can appear a couple of times by chance.
As a result, all the original gene-editing systems had known rates of what are called off-target effects, in which they simply edit the wrong sequence. This may be a low-probability event, but edit enough cells—and therapies generally have to edit many—and errors become inevitable.
A lot of effort has gone into finding ways to minimize or eliminate off-target edits. In a recent issue of Nature, researchers described modifying the AI protein-folding software AlphaFold to help identify key areas of gene-editing proteins responsible for off-target effects. Those areas were then modified to reduce the problems.
When an individual is born with genetic defects, there are a few ways to deal with the impact of the faulty genes. The most extreme solution is direct DNA editing to repair the mutation, while the treatment of symptoms with medication is the least invasive, though this comes with its own set of disadvantages. Antisense therapy keeps a middle ground here, by targeting the messenger RNA (mRNA) that forms the bridge between DNA and the translation into a functional protein by the ribosome.
In a recent study by [Olivia Kim-McManus] et al. antisense therapy with an allele-specific feature was demonstrated in two individuals with SCN2A mutations. These mutations had resulted in severe epilepsy and developmental disorders, due to how instrumental this gene is for normal functioning of the human central nervous system (CNS) where it regulates the initiation of action potentials.
Although SCN2A mutations are rarely inherited, for the approximately 1 in 80,000 affected the consequences can be quite dramatic. The two major types of mutations are classified as gain-of-function (GoF) and loss-of-function (LoF) with respectively hyper- and hyposensitivity of the resulting NAv1.2 sodium channels.
This translates especially in the case of GoF mutations into various symptoms, ranging from mild to severe (daily) epileptic attacks starting as an infant, stalled neurodevelopment and various types of autism (ASD). Often sodium channel blockers are prescribed for the GoF cases to limit epileptic attacks.
Usually with the responsible mutations only a single copy of the gene is affected, so while regular antisense therapy could be used, this would risk also modifying the healthy SCN2A mRNA copy. To get around this, an individualized treatment was developed, targeting the allele with the mutated gene for the two patients in the study: 9- and 14-year old boys with severe developmental and epileptic encephalopathies (DEE) that had left them with daily seizures and despite sodium-channel blockers and other typical medications.
Study outcome of the 14-year old boy with DEE after ASO therapy. (Credit: Kim-McManus et al., Nature Medicine, 2026)
During the trial, the 9-year old boy received 12 doses over 24 months of antisense oligonucleotides (ASOs) adapted to his affected allele, allowing for the cessation of the anti-seizure medication phenytoin, with an overall reduction in seizures. In the case of the 14-year old boy 8 doses were administered over 16 months, resulting in an average of two seizures a day being reduced to zero.
Although the focus of the study was on treating these seizures, by addressing the underlying cause of faulty mRNA transcriptions, changes in the neurodevelopmental state could also be observed. In particular language and motor skills improved, with erratic and irritable behavior reducing. The by then 15-year year old boy was able to walk unassisted, showing clear progression from the previous infantile state.
The advantage of ASOs over typical anti-seizure medication is of course that it directly addresses the faulty mRNA and thus the resulting faulty sodium channels. Since ASOs tend to hang around in a cell for a considerable amount of time, they could be quite a viable alternative treatment even for less severe cases. Whether early application of individualized ASOs in affected infants could lead to a more or less normal neurodevelopment would also be an interesting study question.
Naturally, directly addressing the faulty gene or upregulating the healthy gene would be the ideal and permanent solution, with research here also underway in mice models with the use of CRISPR-based tools.
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