Researchers at Tel Aviv University have developed an innovative gene therapy that may help children suffering from Derva syndrome – a severe developmental epilepsy resulting from a mutation that is not inherited from the parents, but occurs randomly in the fetus, in a gene called SCN1A. The syndrome manifests itself in severe epilepsy that does not respond to medication, along with developmental delay, cognitive impairment and a high chance of early death.
A common disease among the rare genetic diseases
The research was conducted under the leadership of Dr. Moran Rubinstein and the student Saja Padilla, from the medical school and Sagol School of Neuroscience, and Dr. Eric Kramer, from the University of Montpellier in France. Also participating in the study: Anat Mebshev, Marina Bruzel and Keren Anderson from the School of Medicine and the Segol School of Neuroscience at Tel Aviv University, and other researchers from France, the USA and Spain. The article was published in the Journal of Clinical Investigation.
“Darva syndrome, which has a frequency of approximately one in 16,000 births, is considered relatively common among rare genetic diseases. Currently, there are approximately 75 children living in Israel who suffer from Darva. It is a severe developmental epilepsy that begins with febrile convulsions around the age of six months, and progresses after the age of one year , to frequent spontaneous epileptic seizures alongside motor and cognitive developmental delay,” explains Dr. Rubinstein.
According to her, the existing drugs for epilepsy do not sufficiently help children with Derva, and they are at a significant risk of early death. It is known that the severe syndrome results from a genetic mutation that is not inherited from the parents, but is created randomly in the fetus in a gene called SCN1A. In addition, the disease does not characterize a certain segment of the population, it cannot be predicted in advance, nor can it be discovered during pregnancy.
What do you do when it is difficult to make an early diagnosis?
According to the researchers, it is now common to carry out a genetic analysis for children who suffer from complex febrile convulsions around the age of six months. “However, even if the test detects that the problem is in the SCN1A gene, the final diagnosis is often given after the epilepsy worsens – the appearance of severe spontaneous seizures and developmental delay,” they say.
Another problem raised by the researchers is that “although early diagnosis is very important, the diagnosis is often delayed, and most children are only diagnosed at the age of one or two years and sometimes even later. Recently developed genetic therapies have been found to be effective in mice in the Ladarva model, and some of them are even now in the clinical trial phase in humans. However, these treatments have shown efficacy in model mice only when given at very early stages, even before symptoms appear. Since gene therapy is a complex and invasive procedure, it will not be given to children without a certain diagnosis. Therefore, in this study, taking into account the age at the time of the final diagnosis, We concentrated on developing a treatment that would be effective after the onset of seizures, even at a later age. In addition, since the syndrome also includes developmental delay, we sought to develop a treatment that would alleviate both the epilepsy and the cognitive symptoms.”
“In genetic therapies, it is customary to use viruses as carriers that carry normal genetic material into the patient’s body, in order for it to be added to the damaged DNA and enable normal activity. For this purpose, the virus is engineered: its original genetic material is removed from it so that it cannot cause disease or replicate itself, And instead, the relevant normal gene is packaged inside it. In the case of Derva syndrome, it is the SCN1A gene, which is a very large gene, and therefore it was not possible to use common viruses that are usually used for this purpose, and a virus that is capable of carrying and transferring large genes was needed. In our research, we solved the problem on By using a virus called Canine adeno virus type 2, as a carrier of the normal gene,” explains Dr. Rubinstein.
Dr. Moran Rubinstein
Promising results in the laboratory experiment
As part of the study, model mice were treated with a virus carrying a normal SCN1A gene, and the treatment was found to be effective in a variety of critical aspects: improvement in epilepsy, protection from early death, and significant correction of cognitive abilities.
In the next step, the researchers injected the carrier virus into several areas of the brains of the model mice in order for it to infect the damaged nerve cells. 31 mice were treated at 3 weeks of age, after the onset of spontaneous convulsions (equivalent to 1 to 2 years of age in sick children), and 13 mice were treated at 5 weeks of age (equivalent to approximately 6 to 8 years of age in children). In addition, an empty virus was injected into the brains of 48 mice for control.
The results were promising. The highest efficacy was observed when the treatment was injected at 3 weeks of age. In these mice, the convulsions stopped completely within just 60 hours of the injection, life expectancy increased significantly, and the cognitive impairment (diagnosed using spatial memory tests) was fully repaired.
Even in mice treated at 5 weeks of age, a significant improvement was observed, which was manifested in a decrease in epileptic activity and protection from febrile convulsions. In the control group mice that received an empty virus, no improvement was observed and they suffered from the symptoms of the disease just like mice that were not treated at all, and about 50% of them died an early death as a result of the severe epilepsy. In addition, the treatment was injected into healthy mice and did not cause them any harm – proof of its safety.
“Our treatment added a normal gene to the damaged nerve cells in the brain, which was enough to restore them to normal function. The return of the normal gene in its entirety is particularly important in Derva syndrome, because in different children the mutation occurs in different places in the gene, and the complete gene constitutes a single treatment suitable for all patients. In addition, we found that the virus chosen for the purpose “The study infects many nerve cells in the brain, and spreads widely beyond the injection site,” the researchers explain.
“The treatment we developed is the first to be proven effective for Darva syndrome when given after the onset of spontaneous convulsions, and the first to result in an improvement in the cognitive function of the model mice. We have registered a patent for it, and we hope that in the future it will reach the clinic and help children suffering from the serious disease. In addition, we are currently examining whether it may to adapt to other genetic neurodevelopmental diseases as well. The platform we developed is a plug & play platform for genetic therapies, and perhaps in the future we will be able to pack in the carrier virus also normal genetic material of another type, to treat additional diseases,” concludes Dr. Rubinstein.
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