gene therapy technique targeting overactive brain cells shows promise in treating drug-resistant form of disease

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Some 50 million people worldwide suffer from epilepsy. While the majority of these people are able to use medication to manage and prevent their seizures, about a third do not respond well to these treatments. In such cases, the only option available to control the seizures is to remove the part of the brain where the seizures occur. But this procedure is extremely risky.

Since epileptic seizures are caused by excessive activity of brain cells (neurons) in specific parts of the brain, being able to target these neurons and turn them off could very well prevent seizures from occurring.

Thanks to a new innovative gene therapy approach that we have developed, we have been able to show in cellular and animal models that it is possible to specifically target the neurons responsible for epileptic seizures. This then prevented them from becoming hyperactive and causing seizures in the future.

This discovery not only has major implications for the treatment of drug-resistant epilepsy, but there is also the possibility that it could be used to treat other neurological conditions caused by overactive neurons, including Parkinson’s disease and migraines. .

Genetical therapy

Gene therapy works by directly modifying a person’s genes in order to treat a disease or condition. There are different ways to do this.

Previous studies that have used gene therapy to treat epilepsy in animal models have done so using a virus that has been modified in the lab so that it is no longer harmful. The researchers would inject the virus into the region of the brain where the seizures occur. The virus would then implant sections of DNA into the cells, effectively modulating their functioning, making them less active and preventing seizures.

Although this technique is much less invasive than brain surgery, the problem with the method is that it affects all neurons in the brain region – not just those causing the seizures. It also permanently alters the properties of cells that take up DNA delivered by the virus, which can permanently alter brain function.

But our innovative new gene therapy tool has shown that it is possible to modify only the brain cells that cause seizures, without affecting nearby healthy neurons. We were able to do this by taking advantage of how gene expression is normally regulated.

An image of several DNA strands.

The role of promoters

The approximately 20,000 genes we have in our bodies each contain instructions for making different proteins and molecules. These genes are usually under the control of neighboring DNA segments, called promoters. These determine if and how much of a particular protein is made. Different cells express different proteins depending on active or inactive promoters.

There is also a special type of promoter (called an “activity-dependent” promoter) that will only activate in response to biochemical signals emitted by neurons when they fire intensely, such as during a seizure. We have taken advantage of these activity-dependent promoters to create a gene therapy that detects and decreases the excitability of neurons that cause seizures. We did this by coupling activity-dependent promoters to DNA sequences that contain proteins that quiet neurons.

We first tested the gene therapy tool on neurons grown in a dish and then on mice with drug-resistant epilepsy. We have also tested this technique in human “mini-brains” cultured in the laboratory.

Read more: Scientists grow brain tissue with different regions in the lab

In each test, we were able to show that this new gene therapy technique was effective in calming overactive neurons involved in seizures, while leaving healthy control cells intact.

Although it takes about an hour to activate – longer than the usual duration of a seizure – the new gene therapy is very effective in preventing future seizures. To do this, it automatically selects the neurons to be treated and turns them off. It is also able to return neurons to their original state when brain activity returns to normal. If the seizures happen again, the promoter is ready to turn on.

The treatment therefore only needs to be administered once, but has a long-lasting, possibly lifelong effect. Importantly, the treatment did not affect the mice’s performance in tests of memory and other normal behaviors (such as their levels of anxiety, learning and mobility).

We are excited about this breakthrough because it could in principle offer the prospect of gene therapy to a wide range of people with drug-resistant epilepsy. But before the therapy is ready for use with these patients, we’ll need to put it through a number of tests to see if it can be extended to larger brains.

This article is republished from The Conversation under a Creative Commons license. Read the original article.

The conversation

The conversation

Gabriele Lignani consults/holds shares in a company that aims to bring gene therapy for epilepsy to the clinic. He has received funding from Epilepsy Research UK and the Medical Research Council.

Dimitri Kullmann is a consultant/stockholder in a company that aims to bring gene therapy for epilepsy to the clinic. He has received funding from the Wellcome Trust and the Medical Research Council.

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