The epileptic encephalopathies (EEs) are characterized by frequent seizures and cognitive and behavioral impairment. The presence of the mental handicap is a signal that the EEs origin during the neuronal development, so that, even if the seizure can be controlled by using available anti-epileptic drugs, the cognitive impairment cannot be stopped with the current treatments. This is the reason why the EEs are considered neurodegenerative and neurodevelopmental diseases at the same time.
The malfunction of the syntaxin binding protein 1 (STXBP1) is considered a key factor triggering the EEs. Depending on the type of mutation in the corresponding STXBP1 gene, the EEs show different symptoms: while the 95% of the patients with mutations in the STXBP1 gene show epilepsy, other clinical symptoms show a broad range of variability.
Pathophysiologic mechanisms of the STXBP1 protein
The STXBP1 protein seems to have an important role at the level of the synaptic vesicles. Indeed, it binds to the SNARE protein complex in a way that helps the fusion of the synaptic vesicles membrane with the plasma membrane, thus allowing the neurotransmitters contained in the vesicles to be released in the synaptic space.
The mutations in the STXBP1 gene are dominant, that is, their effect appears in heterozygotic conditions: just one copy of the two genes is enough for the development of the disease. Moreover, different mutations have different effects on the pathogenesis of the EEs: the STXBP1 protein may be totally absent, thus preventing the survival of the neurons, or may be present at lower concentrations than the normality, leading to many different pathologic conditions, or may be present at normal levels, but with impaired biological functions depending on how its tridimensional structure has been affected by the mutations.
So, the consequences at the pathogenic level are very variable: the seizure is often present, but the neurodevelopmental impairment varies a lot. The animal models for the study of the EEs not always helps the researchers as, in many cases, animals without the STXBP1 gene do not develop epilepsy symptoms (while some models, like the zebrafish, seems to show seizure).
Current therapies and future possibilities
To date, the use of anti-epileptic drugs is the only way to deal with the STXBP1 malfunction. The majority of patients have their seizure controlled, and one out of three patients can achieve the total absence of seizure. This kind of drugs, however, are able to control the seizure but do not remove the cause of the disease, because they do not act directly against the STXBP1. However, in a not far away future, the target of the drugs will be focused exactly on the STXBP1 with the goal to intervene on the developmental aspects of the EEs.
The most promising treatment is called gene therapy: the idea is to substitute the defective STXBP1 gene with its functioning copy. The gene can be inserted into the neuronal cells by an injection of not infective viruses containing the functioning gene (for example, serotypes of neuron-specific Adeno-Associated Viruses), or by other molecular biology techniques virus-free.
The main drawbacks in using the gene therapy are the risk of an immune response that against the virus proteins, or the possible insertion of the gene in zones of the genome that may alter the functions of other regulatory genes associated with the development of cancer.
However, the recent advances in the molecular techniques, such as the genome editing by the CRISPR system, are likely to minimize the negative impacts of the gene therapy, in fact, few clinical trials have already started in patients.
The importance of the early screening
It is also important to notice that the new therapies should be applied before or at the very early stages of the EE diseases in order to be effective in the neurons development protection. For this reason, it should be important to find adequate biomarkers for a fast screening but at the moment, validated biomarkers are still lacking. This is true for all the neurodevelopmental diseases, such as the Rett syndrome or the Fragile-X syndrome. So that, the correct, narrow time window for starting the therapy will be fundamental.
Moreover, a registry for the patients with pathologies related to the STXBP1 has been created (http://stxdisorders.org) in order to have a fast tool to identify the patients, for example, when a new compound or a new therapy is available. This could be useful to contact the potential targets and accelerate their inclusion in future clinical trials.
In Europe, the annual cost for the epilepsy treatment is of 13.8 billion euro and 43.3 billion euro for intellectual disability. This amount of money is a burden that could be lightened thanks to the research progress, not to mention the great importance of improving these conditions in patients. Gene therapy, the findings of early-stage disease biomarkers, basic neurodevelopment studies and new drug compounds research are the keywords for the upcoming medical approaches for the EEs.
Stamberger H. et al. STXBP1 as a therapeutic target for Epileptic Encephalopathy. Expert Opinion on Therapeutic Targets 2017 Nov;21(11):1027-1036
The elaboration of this post has been financed by the project PI15/01082, as a part of the National Plan of I+D+I and co-financed by the ISCIII – General Deputy Direction for Evaluation and Development of Health Research – and the European Regional Development Fund (ERDF).