Pharmacological therapy of autism

Autism spectrum disorder (ASD) represents a heterogeneous group of neurodevelopmental disorders that affect 1-3% of the population and are a significant burden for each individual. Despite ASD occurring relatively often in the population and negatively impacting life quality, there are still no medical drugs targeting its characteristic symptoms.

Why is this the case?

One of the biggest challenges is the clinical and biological heterogeneity of the disorder. Even the basic symptoms such as lack of social skills and restricted, repetitive behavioural patterns, span over a broad spectrum due to pronounced individual differences. In addition to neurological impairments, ASD causes other organ-system dysfunctions too. Hence, it is even more difficult to form the hypothesis and to determine the correct way of recognising behavioural patterns that can change biologically, regardless of the underlying aetiology.

Another major issue is the influence of various environmental and genetic factors on the development of the disorder. Hundreds of different genes and their variations have been recognised as factors contributing to the ASD progression. Most of these mutations are not inherited from parents, but they still have multiple unrelated effects on various organs resulting in different phenotypes depending on each individual.

Moreover, all of those factors significantly complicate the identification of a potential specific target and its validation through behavioural or biological markers.

Existing therapy

The antipsychotics risperidone and aripiprazole are currently the only specific drugs approved by the FDA, while the EMA has not approved any such drug yet. They are used for reducing irritability and aggression, but they do not address the crucial symptoms. Additionally, their long-term use leads to the undesirable side effects such as weight gain, insulin resistance, and dyslipidaemia, thus increasing the need to develop new drugs.

It is common to use antidepressants, psychostimulants, and other antipsychotics as nonspecific therapy in addition to the specific drugs in an attempt to alleviate other characteristic symptoms.

Development of new drugs

To be able to develop new medications, it is necessary to elaborate on pathways involved in the development of the nervous system, metabolism and the immunoregulation, as their alteration affects the development of ASD. Most importantly, it is crucial to identify the connections between these pathways, as they represent the most ideal targets for new drugs.

We currently know that ASD affects pathways involved in CNS development, neuron proliferation and migration, as well as it is involved in kinase signalling pathways, transcription regulation, cytoskeleton, microtubules, adhesion molecules, chromatin regulation and glycosylation. Based on these findings, genetic variants of autism are grouped into those affecting the:

1. Transcriptional regulation and kinases involved in cellular signalling (MAPK, mTOR, Ras, …)
2. Chromatin remodelling
3. Synaptic function (ion channels, receptors, cytoskeleton)

Thus, existing and developing pharmacological treatments can be divided into three groups based on their mechanism of action.

Drugs that regulate transcription

The main focus of recent research has been the manipulation of transcription regulators. Ras, mTOR, and MAPK signalling pathways, in addition to their participation in cancer cell growth, are the key to CNS development and the ability of synapses to strengthen or weaken depending on their activity. Nowadays, insulin-like growth factor 1 (IGF-1) shows promising results. Stimulating the IGF-1 receptor activates the mTOR and MAPK pathways, resulting in transcription of proteins important for maintaining neurons and synaptogenesis. Another equally promising pathway is the inhibition of kinases needed for phosphorylation of enzymes involved in neurotransmission, one such kinase is the glycogen synthase kinase 3. Inhibition of this kinase achieves mood stabilisation in patients suffering from bipolar disorder. Tideglusib,  which is a drug that helps in improvement of social skills, repetitive behaviour, and adaptive functioning, acts in this manner.

Drugs that remodel chromatin

Inhibitors of histone deacetylases (HDAC) affect the change in chromatin structure. These enzymes participate in the formation of transcription-inactive chromatin, and their inhibition leads to the activation or suppression of certain genes. HDAC inhibitors have been used as cytostatics, but some preclinical studies have shown that they exert pro-cognitive and antidepressant effects. These findings have later been confirmed in genetically modified mice whose social deficits have been significantly improved after administration of AR-42, a new HDAC inhibitor.

Drugs that affect synaptic function

Most of the drugs that have been tested so far, regardless if they are new or repurposed, affect the synapse in some way. Their mechanism is based on the hypothesis that ASD results from an imbalance between excitatory and inhibitory signals. These drugs are mainly antagonists of glutamate receptors (excitatory neurotransmitter) and agonists/antagonists of GABA receptors ( GABA-inhibitory neurotransmitter). Examples include memantine, ketamine, and amantadine, which act as NMDA receptor antagonists. Arbaclofen and bumetanide, which have a GABAergic effect, are also included in this group.

On the other hand, some drugs give contrasting results, improving one group of symptoms while simultaneously worsening another. These results suggest the need for an individualised approach to treatment in which the therapy is based on the genetic variant of autism.

The nervous system is not the only system affected by ASD. There have been numerous recordings of changes in the function of the immune system in patients, especially in children. Results vary with age, sex, and individualism. However, statistically, those with ASD have elevated levels of pro-inflammatory cytokines in serum. For this reason, many immunomodulators and anti-inflammatory drugs are being investigated for treating autism. In addition, the innate immune system plays a crucial role in prenatal development of the nervous system.

Why is the development of specific drugs for ASD important?

ASD is a complex disorder that poses a major challenge for research. Cases are becoming more and more frequent and severe, but the available specific therapy is practically nonexistent at the moment. For this reason, to enable the best possible life quality and increased functional ability for individuals on the spectrum, the research must be continued and encouraged regardless of the obstacles along the way.

Translated by: Dea Radek