Head of Research in Genetic Encephalopathies

Like any other biological process, brain function is controlled by the coordinated action of thousands of genes in our body. But in many cases, the failure of a single gene has catastrophic consequences for the life of the affected person and their environment. For example, it is estimated that up to 50% of epilepsies that begin before the age of three may be caused by mutations in a specific gene (monogenic disease).

Giving up is not an option

In many cases, a diagnosis of one of these diseases carries a bleak outlook for quality of life and therapeutic options. But patients and their families are not ready to give up. They are working hard not only to ensure access to the best medical care to alleviate the effects of the disease, but also to discover new paths to healing. And to do this, they count on doctors and scientists as indispensable allies.

One disease that is particularly representative of this alliance is Dravet syndrome, an encephalopathy that, among other manifestations, causes drug-resistant epilepsy, cognitive deficits, movement disorders, and hyperactivity.

Since its definition as a clinical entity and the subsequent identification of the responsible gene (SCN1A), progress in understanding the disease and the discovery of new therapeutic options have increased at a dizzying rate.

Center of Interest

In addition to the invaluable influence of patient associations, there are several factors that contribute to this interest. On the one hand, its incidence is relatively high against the background of monogenic diseases (one case in every 16,000 births), a factor that is increasingly taken into account in the biopharmaceutical sector.

On the other hand, its pathophysiology (the biological mechanism that causes the disease) is compatible with a wide range of gene therapy methods.

In patients with Dravet syndrome, only one of the two copies of the SCN1A gene is mutated. Therefore, one therapeutic option is to increase the efficiency of the healthy allele. This can be achieved by introducing a small amount of genetic material (antisense oligonucleotides) that can be delivered to the brain via a lumbar puncture.

Stoke Therapeutics is conducting clinical trials with promising results not only in reducing epileptic seizures, but also in other aspects that profoundly impact patients’ quality of life.

Another method of stimulating the function of the healthy allele is to express activators specifically designed for the SCN1A gene. In this case, a gene therapy vector (transport mechanism) derived from the adeno-associated virus (AAV) is needed, since the genetic material is too large to overcome biological barriers. Encoded Therapeutics plans to begin clinical trials of this strategy this year.

Transferring healthy copies of genes (or rather, their coding regions) is one of the “classic” methods of gene therapy. However, the length of SCN1A (6,000 base pairs) exceeds the capabilities of AAV vectors, which are currently most widely used in the brain.

Promising progress

For this reason, several laboratories, including ours at CIMA, University of Navarra, are developing complementation strategies using pairs of vectors. We have also shown in animal models of Dravet syndrome that high-throughput adenovirus-derived vectors can transfer the complete coding sequence of SCN1A into neurons. Confirming that this reduces some of the symptoms of the disease was a very important and promising achievement.

These and other strategies being developed in parallel allow us to hope for a significant improvement in the treatment of Dravet syndrome in the medium term, provided that social, institutional and industrial support for research is maintained.

Although Dravet syndrome is susceptible to several mechanisms of action of gene therapy, it also requires the highest level of precision and efficiency. It is necessary to achieve physiological expression of the SCN1A gene above the therapeutic threshold, but without reaching excessive levels.

And if that weren’t enough, the gene modification would likely occur preferentially in the appropriate type of neuron and in large areas of the brain. Advances in this disease could therefore be key to treating many other genetic encephalopathies.

Many professionals from different fields continue to work with such enthusiasm, thanks to the invaluable support of patients and their families.