Benito Maffei / University College London
Gabriele Rignani
Associate ProfessorUniversity of London
Dimitri Kullman
ProfessorUniversity of London
Precision is key when it comes to treating brain-based diseases. Therapies that indiscriminately upregulate genes or attenuate neuronal activity in diverse cell types can be counterproductive.
Precision medicine is particularly important for epilepsy, one of the most common comorbidities in people with autism. Only some groups of neurons are overactive during a seizure, so there’s no need to shut down all of them, says Gabriele Lignani, an associate professor of clinical and experimental epilepsy at University College London in the UK.
Rignani and his colleagues have developed a new gene therapy tool that switches on only in overactive neurons to temporarily dampen overactivity. The result is a therapy that “works when you need it and doesn’t when you don’t,” says his Dimitri Kullmann, co-principal investigator and neurology professor at the same university.
A new approach successfully suppressed hyperactive neurons and brain organoids in mice that model chronic epilepsy, limiting seizures, the researchers showed in a study published in November. chemistry.
Rignani and Kurman spectrum about how their new gene therapy approach works and how it could one day be used to treat other diseases as well.
This interview has been edited for length and clarity.
spectrum: How does your approach selectively target seizure-associated neurons?
Gabriele Rignani: We designed viruses that carry promoters (regions of gene coding that can enhance the expression of nearby genes) and therapeutic transgenes. The virus infects neurons and its promoter, called C-FOS, can sense increased neuronal activity through an increase in intracellular calcium. When that happens, the promoter quickly switches on the transgene that encodes the potassium channel Kv1.1. Increasing expression of this channel reduces neuronal excitability. This creates this closed loop. Increased activity activates the promoter. This leads to an increase in potassium channels in the cell membrane, reducing future activity levels of the cell.
S.: What did we learn when we tested this treatment in mice?
Dimitri Kullman: Mice were treated with either this virus or a control virus carrying a promoter driving a fluorescent protein. The animals were then given a seizure-inducing stimulus.
When we first did that, there was no difference between the groups because it takes time for the treatment to switch on.Potassium channels are expressed at higher levels and limit cellular activity.But 24 When returned an hour later and given a second stimulus to induce seizures, animals expressing the C-FOS promoter driving potassium channels were protected. Fewer seizures than the control group.
S: How long does the effect last?
DK: It doesn’t last forever. When the seizure is over, it basically automatically switches itself off. When the same animals were tested two weeks later, the treatment was turned off when there were no seizures in between, so when he gave the animals a third stimulus to induce seizures, the two There were no differences between groups.
S: What are the benefits of fading over time?
DK: I am a neurologist and see epilepsy patients. Also, in the clinic, some people go into remission. I don’t really know why, but sometimes my epilepsy gets better. As a general rule, people should be able to stop treatment once whatever caused the epilepsy in the first place is gone.
The C-FOS promoter and potassium channel transgene still remain in neurons. But it’s like someone said. You can stop taking it, but keep it in case seizures recur. Of course, unlike drugs, this approach doesn’t soak the entire brain or affect other cells. It targets only specific neurons.
S.: What about mice that model chronic epilepsy?
GL: This is a spontaneous generalized seizure model mouse developed in our laboratory. Treating them with this approach reduced the number of spontaneous seizures by more than 80% when tested two weeks after treatment onset.
DK: In this case, treatment is likely to continue with what is called an “interictal spike”. These are small bursts of non-seizure activity that occur in the brains of many people with epilepsy. And those spikes were probably enough to keep the treatment going, so I don’t think it completely switched off.
S.: How might this approach help other conditions?
DK: This is speculation to be sure, but the idea is that people who have a psychotic episode and then develop chronic schizophrenia have hyperactivity in certain parts of the temporal lobe. , this therapy may be a way to interrupt that activity and prevent the progression from psychosis to chronic schizophrenia.
Researchers also speculate that autism may be a condition characterized by an imbalance between excitation and inhibition. You have to be very careful.
GL: My vision for this therapeutic approach is a compensatory mechanism that seeks to rebalance a dysfunctional network. So from an autism perspective, if there is an imbalance in brain activity during neurodevelopment, something like this might re-stabilize activity and resume brain development in a typical way. .
S.: What is the next step for this project?
GL: As a first step, we are working to bring this treatment closer to clinical trials in epilepsy.
DK: And we want to see if it works in other models of epilepsy and other diseases.
Citing this article: https://doi.org/10.53053/QUDY6689
