Autism

Jig­saw piece for the the­rapy of rare ge­netic disea­ses

Many human cell types have a precise calcium uptake mechanism. One gene in which part of the blueprint for these so-called calcium channels is encoded is also partly to blame for a rare human developmental disorder that triggers epilepsy and autism. The research group led by Joerg Striessnig is exploring these links and working on a potential form of therapy.

In the human body, calcium is a strictly regulated substance. Not only vital for bones and teeth, the mineral also plays an essential role in the function of muscles, in the cardiovascular system, the hormone balance or the nervous system. Many human cell types have a specific mechanism for admitting an exact amount of charged calcium ions when required. When these cells are electrically excited, so-called calcium channels open for fractions of a second – small pores that only permit ions of this element to slip through. This mechanism is also involved in other functions, for instance in the heart muscle cells when it comes to the organisation of a regular contraction of the heart, i.e. the heartbeat.

Jörg Striessnig, professor in the Department of Pharmacology and Toxicology at the University of Innsbruck, has been studying the calcium channels of human cells since the early 1980s. Among other things, his working group has investigated how the opening and closing of the channels by electrical excitation actually works and in what way this mechanism is influenced by drugs. Thanks to advanced molecular biological research methods, the researchers have been able to relate certain problems in the regulation of the channels to rare genetic diseases that trigger developmental disorders in children, autism or epilepsy. In an ongoing project funded by the Austrian Science Fund FWF, Striessnig and his colleagues are trying to find out even more about these connections and to identify potential forms of therapy.

Spontaneous gene mutations trigger diseases

“Using powerful next generation sequencing, we can capture the genetic information of a person quickly and comparatively cheaply,” Striessnig explains. “This also facilitates easier characterisation of genetic diseases that have not been inherited but are a consequence of spontaneous mutations – we refer to them as ‘de novo mutations’.” The rapid sequencing methods and novel bioinformatic evaluation options enable researchers to identify more and more human genes that can trigger congenital developmental disorders when defective.

In this way, a gene called CACNA1D has been identified as a risk factor for the development of autism. CACNA1D is also well known to Striessnig and his team from their calcium channel research, since the gene is responsible for the production of a protein that controls the opening and closing mechanism of a specific type of calcium channel called Cav1.3.

Using cell culture models, the scientists have now been investigating what functional change the gene defect that is responsible for the developmental disorder triggers in the calcium channels. “We have found that there is a change in the way the calcium channel opens and closes,” notes Striessnig, summarising the result of this investigation. “The genetic defect activates these calcium channels and boosts their function.”

Genetic developmental disorder causing epilepsy and autism

There are not a huge number of people whose disease is based on a CACNA1D genetic defect. Striessnig's working group is in contact with about twelve families worldwide who have a child showing developmental disorders caused by this defect. In most cases, the clinical picture includes marked intellectual impairment and epilepsy – in some cases autism and auto-aggressive behaviour. “It is a very rare disorder, but it is also definitely underdiagnosed and new cases are constantly being added,” Striessnig explains.

In order to test a therapy, the researchers are now using existing drugs which interfere with the mechanism related to the calcium channels – but which were originally used for a completely different purpose: the treatment of high blood pressure. These “calcium channel blockers” enable a molecule to dock to the calcium channel, which inhibits the uptake of the substance. As a consequence, the arteries slacken and the heartrate is lowered in terms of intensity and frequency of the heartbeat – and with that, blood pressure drops as well.

Cautious testing of existing drugs

The researchers are now exploring the following question: can these drugs also be used for the above-mentioned developmental disorders to reduce the activity gain of the calcium channels? Previous studies by the Innsbruck-based research group have shown that the sensitivity to the calcium channel blockers increases as a result of the heightened activity caused by the genetic defect. This gives Striessnig confidence, and he and his team are now in the process of encouraging the families and the physicians treating the young sufferers to agree to a cautious trial of the new therapy approach. “We first have to test our way carefully to the right concentrations of the active substance that will inhibit calcium uptake to the right extent,” Striessnig explains.

But even if this approach works, Striessnig warns against expecting a complete cure. What one might see, however, is a reduction of the symptoms: there may be less frequent epileptic seizures, the ability to communicate could improve and the auto-aggressive behaviour might decrease. Such progress would be enormously important for the situation the patients and their parents find themselves in. As Striessnig reports, a first milestone is in sight: “Before the end of 2021 we want to be able to determine whether the currently existing drugs can be administered safely to children.”

Personal details

Jörg Striessnig is head of the Department of Pharmacology and Toxicology at the Institute of Pharmacy, University of Innsbruck. During his postdoctoral position at the University of Innsbruck, which he started in 1984, this native Tyrolean already started to investigate the function of calcium channels in human cells. As a Visiting Assistant Professor at the University of Washington in Seattle, he was able to intensify this research before returning to the University of Innsbruck, where he was appointed full professor in 2001. The project “Cav1.3 L-type calcium channel dysfunction in human disease” is funded by the Austrian Science Fund FWF with roughly EUR 440,000.

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