A new gene therapy from a team of cell biologists at University College London promises to target overactive brain cells and treat neurological disorders and psychiatric diseases characterized by overactive neurons. This is the case for many brain diseases, such as epilepsy, which often do not respond well to drug treatments. This new gene therapy, described in the journal Science, appears to be able to distinguish between overactive and normal brain cells.
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Epilepsy
Although previous research has shown that gene therapies hold promise for treating these neurological conditions, these methods cannot distinguish between diseased and healthy brain cells. The gene therapies that have been already tested, like the currently available drugs, affect the entire brain.
New therapies targeting hyperactive and autoregulatory neurons
Lead author Dr. Gabriele Lignani, a researcher at the UCL Institute of Neurology, points out that gene therapy is only activated in hyperactive cells and inactivated when activity returns to normal: the therapy exploits the ability of certain DNA sequences to regulate gene expression in response to metabolic signals. If this activity-sensing mechanism is redirected to control the production of molecules that prevent brain cells from firing, the risk of hyperactivity becomes controllable. In particular, epileptic seizures can be suppressed.
The study
The team of researchers analyzed a number of genes known to be activated by stimulation and linked their promoters (DNA sequences that determine whether DNA is copied to RNA) to potassium channels that have been selected for their ability to reduce nerve cell firing. These promoter/potassium channel combinations were tested in vivo in mice and in vitro in laboratory-grown miniature structures or organoids resembling mini-brains.
An immediate promoter combination of the c-Fos gene and the potassium channel gene KCNA1 was identified which is very effective in attenuating neuronal excitability after induced seizures, but also after spontaneous seizures.
This gene combination does not cause negative side effects on cognition in animal models of seizures.
the therapy appears to be more effective than previous gene therapies or antiepileptic drugs tested in the same model, and results in a reduction of spontaneous seizures in epileptic mice of about 80%.
Taken together, these data suggest that this gene therapy could be used in other disorders in which certain brain cells are overactive, such as Parkinson’s disease.
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The results of the study demonstrate that it is possible to normalize brain cell activity and that this approach can be used to treat other drug-resistant neuropsychiatric disorders. Furthermore, this gene therapy is self-regulating and can be used without the need to predetermine which brain cells it targets.
References
On-demand cell-autonomous gene therapy for brain circuit disorders
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