Playing with neuronal fire
Like a thunderstorm in the brain that discharges uncontrollably - the condition that patients experience during epileptic seizures is hard to control, especially in complex cases. A new approach has emerged from the biotech lab: so-called organoids, which can be used to artificially reconstruct brain regions. Now they have arrived in the clinic. Martha Feucht, head of the Epilepsy Center at the University Clinic for Pediatrics and Adolescent Medicine at Vienna General Hospital, tells medinlive.at how research on cerebral organoids is changing the path from bench to bedside.
Tuberous sclerosis is rare, complex and difficult to control with medication. . This neurological disease is the focus of a study tha started two years ago as a collaboration between the biotechnology company IMBA (Institute for Molecular Biotechnology of the Austrian Academy of Sciences) and MedUni Vienna/AKH. The IMBA researchers have recreated a subsection of the disease pattern in three-dimensional brain models made from reprogrammed stem cells from patients. They correspond to the brain of an embryo in its early stages.
medinlive: Dr. Feucht, what is the initial situation regarding the clinical picture of tuberous sclerosis?
Feucht: Tuberous sclerosis (TSC) is a rare genetic disease that leads to tumor formation in various organs, including the brain. These tumors cause various neurological and psychiatric disorders. Around 90 percent of patients with TSC suffer from epilepsy - in the vast majority beginning in the first years of life. Affected infants and young children also tend to develop so-called epileptic encephalopathies (EE) with significant impairment of further development.
medinlive: What approaches have been taken in treatment so far?
Moist: Current therapeutic approaches rely on the one hand on the earliest possible diagnosis (ideally prenatally or immediately after birth), regular EEG screening (electroencephalography, note), and "preventive" treatment as soon as the children develop increasingly specific EEG changes. At present, it is still unclear at which point in time exactly a treatment is useful or necessary.
Finding the ideal moment to start treatment or defining a point of no return, after which a return of the EEG to normal is impossible, was also the focus of an EU project called "EPI Stop", in which the Pediatric Epilepsy Center Vienna at AKH participated. In this project, infants with TSC underwent regular EEG examinations and were randomly assigned to two treatment groups: preventive treatment with an anticonvuslivum already when epilepsy-specific EEG changes appeared or conservative treatment only when seizures occurred. And, although it appeared that preventive treatment was also started too late in this case, the children in the preventive group were found to have less severe epilepsy at the two-year follow-up and to have developed significantly better than those in the conservative treatment group.
Since conventional anticonvulsants are usually not very effective in TSC-associated epilepsies or many patients prove to be pharmacoresistant, the second approach is to find new substances that not only treat the seizures symptomatically, but also modify the course of the disease per se based on current knowledge of the underlying genetic defect and its effects. In this context, tuberous sclerosis now serves as a model for the so-called mTOR mechanism, which the underlying gene mutation (specifically, the TSC1 and TSC2 genes) influences, leading to the development of tumors and the development of epilepsy, respectively. This led to the partly very successful application of so-called mTor inhibitors (use of substances already known from transplant medicine and oncology). However, mTOR inhibitors did not lead to the desired effect in all TSC patients and the overall efficacy in epilepsy - compared to the treatment of tumors in the brain, kidney and lung - was significantly lower than hoped for.
medinlive: What were the considerations behind the "Project Epilepsy" on which you are working together with the IMBA?
Moist: The idea behind it was to be able to study the underlying disease mechanism of TSC in more detail. This is generally not so easy. Although it is possible to study brain tissue from patients after tumor and epilepsy surgery, this approach quickly reaches its limits. Furthermore, testing new substances on infants and young children is generally difficult and limited by ethical constraints.
Therefore, the dual approach of producing an organoid for each patient individually and using it to study the basics of the disease as well as to test possible therapeutic approaches seemed to be an attractive alternative. Specifically, blood cells are taken from patients, converted back into stem cells, neurons are generated from them, and cerebral brain models are produced on which further studies can be conducted.
medinlive: How many subjects were there? What phase is the study in?
Feucht: In a complex and expensive procedure, organoids were produced from three patients who exhibited different characteristics of this disease. Now the first study results are ready and have been compared with those in the tissue of operated patients.
medinlive: What about funding?
Feucht: The project is still funded by a grant from the City of Vienna (the stem cell initiative at IMBA is funded by a grant from the Federal Ministry of Science as well as by the City of Vienna, note). The further financing still has to be clarified. This is also where you notice the hurdles between a purely theoretical institute and a purely clinical department. The question is also how we find the translation from the slide to the patient. That is the most difficult step, namely that it is feasible in terms of time, effort and costs. The effort to do a clinical trial - even more so in infants - is enormous. It is a complicated and lengthy process that requires a great deal of organizational work in advance. This was also evident in the "Epistop" project, for example. Some centers in Europe did not receive permission from their local ethics committee until the end of the project, which lasted five years.
medinlive: Are there any pioneering projects in the field of tuberous sclerosis that can be used as a model?
Feucht: Exemplary was certainly the TOSCA project initiated by Novartis (I was a member of the scientific advisory board here), a disease registry with associated prospective clinical and genetic sub-projects that included data from over 2000 patients with TSC worldwide over an eight-year timespan. The project was extremely successful, and further projects were planned for other diseases in which the mTOR mechanism plays a role. However, following corporate restructuring, the tuberous sclerosis project was terminated. Unfortunately, it was impossible to continue the studies that had been started without the company's further support.
medinlive: What alternatives would there be?
Feucht: So-called "investigator-initiated" studies (studies initiated and planned by investigators or study centers without a primarily commercial interest, note), which are submitted as a request for support to both research funds and pharmaceutical companies, are an alternative. Here it is conceivable that companies may be interested in testing drugs on the organoid. We are very much in favor of this project, because it would lead away from the difficulties of having to do drug studies on very young children. Instead, one could create individual organoids and test them on an aviator.
Parents would also be easier to win over and recruitment would be easier, since apart from the fact that blood samples are primarily required, no further interventions on the child would be necessary.
medinlive: And of course, this could lead to ethical questions, such as how these cells are further used?
Feucht: That's more our problem, because we have very strict ethical requirements that sometimes take a long time to clarify.
medinlive: What are the specific requirements?
Feucht: You have to submit a drug study with background, exact study protocol, efficiency and safety test to the ethics committee. In children, this is a complex and usually lengthy process. If approval is granted, the recruitment of patients in a small country like Austria is extremely difficult. However, if one were to think further, for example, about a Europe-wide collaborative study, one would currently again have the problem with different institutions in different countries and thus enormous costs and loss of time. The creation of European reference networks, whose members commit themselves to cooperate in the treatment, teaching and research of rare diseases, should minimize this problem in the future.
medinlive: At what stage is the Dravet syndrome study?
Moist: This study is at the beginning: Dravet syndrome is a disease that is also genetically caused (the mutation leads to a loss of function/loss of function at the sodium channel). The disease primarily affects the brain (leading to neurological and psychological disorders as well as epilepsies that are difficult to treat), but also the heart (and carries an increased risk of sudden cardiac death). However, specific tissue changes as in TSC are not visible and (epilepsy) surgery is not indicated.
To date, the only effective therapy is avoidance of sodium channel blockers; specific effective therapies do not yet exist. The primary goal of the project would be to gain more detailed information about the disease mechanism at the organoid and thus ideas for innovative therapeutic approaches.
medinlive: But the focus of work with organoids is basically on both areas - investigating causes and generating new therapeutic approaches?
Feucht: That's what connects the two projects. The idea is that I generate knowledge about how the disease works and try to reverse or at least modify the pathomechanism.
medinlive: How have organoids changed the bench-to-bedside process?
Feucht: They bypass the need to directly examine the patient. That would be possible in other diseases as well.
medinlive: In the clinical application of organoids, do you focus on more complex disease patterns?
Moist: Yes, epilepsies are neither monogenetic nor simple. In most cases, they also do not follow Mendel's laws, which means it is insanely difficult to even find the defect. However, with deep sequencing, i.e. next generation sequencing, we are increasingly discovering disease-causing mutations. However, the significance of these mutations for the development of epilepsy is not easy to assess. Here, studies on organoids could certainly generate knowledge.
medinlive: How fragmented is the research landscape in this field?
Feucht: Even where there is networking, there is of course competition, which on the one hand is a driving force, but on the other hand - with resources running out - can also be a hindrance.
medinlive: Have you come across any aspects or developments in this research field that have worried you?
Feucht: No, not so far. What we wanted to know is so specific that I don't see any ethical problem there: To find out more about the cause of the disease in this way (without examining the patient himself), as well as to be able to better define who responds to therapy with an mTor inhibitor (and thus to spare those affected unnecessary side effects from a therapy that is also extremely expensive) or to find treatment alternatives for "non-responders".
medinlive: What are the options when there is no money for clinical trials?
Moist: One can try to do single-cure trials in therapy-resistant severely ill patients if there are no alternatives.
medinlive: To talk about epilepsy in general. You said in an interview with the "Standard" that epilepsy is very often misdiagnosed. How big is this problem?
Moist: We are a grade 4 center, which means that patients only come to us if they have pharmacoresistant epilepsy. In all centers worldwide, you have to reckon with the fact that about 20 percent of the patients who are sent seem to be pharmacoresistant, which means that they either don't have epilepsy at all or the syndrome has been misdiagnosed and therefore the treatment is not optimal. An example here would be to give a patient with Dravet syndrome the sodium channel blocker carbamazepine (a commonly prescribed anticonvulsant, note).
medinlive: What ideas do you have to improve this issue structurally?
Moist: More in-depth specific training. To see that all physicians who are interested in this field and want to work in it on patients acquire the certificate Epileptology plus and an EEG certificate to be able to interpret EEGs correctly. Training in Austria is regulated by societies: both the ÖGKN (Austrian Society for Clinical Neurophysiology, note) and the Austrian Society of Epileptology, the Austrian chapter of the ILAE (International League Against Epilepsy, note). The difficulty for young colleagues who decide to specialize in pediatrics is increasingly the breadth of the field, in which neurology is only one part, while in adulthood there is a separate specialty training in neurology.
medinlive: Finally, let's turn to the current situation. What impact did the coronavirus outbreak have on the daily work in the ward. Do epilepsy patients count as a high-risk group, and were there any considerations or recommendations to discontinue medication?
Moist: For patients with epilepsy, there are well-published recommendations from various societies, now also based on autopsy findings. According to these, epilepsy alone does not pose an increased risk. It is recommended to list patients with fever-associated epilepsy syndromes (e.g. Dravet syndrome) and patients receiving immunosuppressive therapy (e.g. everolimus for TSC, steroids for West syndrome,...) as risk groups.