2023-12-04 15:46:44
New hopes for autism from Italian research. A step forward for the pharmacological treatment of symptoms comes from a study conducted in Milan – not yet on patients – by scientists from the State University, the European Institute of Oncology (Ieo) and the Human Technopole (Ht). The authors found that inhibiting a specific gene (GTF2I) reverses the main manifestations of autism in preclinical models of 7Dup syndrome, a rare genetic neurodevelopmental condition that is part of the autism spectrum disorders. The results were published in ‘Science Advances’ by the coordinated team Giuseppe Testa, UniMi professor of Molecular Biology, director of the Ht research program in Neurogenomics and Ieo group leader, with first authors Alejandro Lopez-Tobon, Reinald Shyti, Carlo Emanuele Villa and Cristina Cheroni.
The researchers – explain from the Milanese University – used pluripotent cells (iPsc) reprogrammed from patients suffering from two neurodevelopmental disorders caused by the alteration of a portion of chromosome 7 (located in the 7q11.23 region) – Williams-Beuren syndrome ( Wbs) and 7Dup syndrome – to generate brain organoids, complex in vitro cellular models that reproduce key aspects of human brain development at a level of molecular precision not achievable with other techniques. “Thanks to very high resolution technologies (single cell omics) and innovative data analysis approaches – describe Villa and Cheroni – we were able to define the impact of the altered gene dosage of the 7q11.23 region on the developmental trajectory in neurons of the cortex in terms of specific populations of neurons which, in the 7Dup condition, follow a different maturation trajectory”.
The scientists thus observed that a gene in the 7q11.23 region, GTF2I which encodes a protein with a regulatory function on many other downstream genes (a so-called transcription factor), was mainly responsible for the alterations in neuronal development. Having previously discovered its mechanism of action, they selected a class of molecules capable of inhibiting its activity, testing the results on the organoid and subsequently on mouse models. In these, the most validated and standardized behavioral tests of sociability (social preference and social novelty) have confirmed that the increased dosage of GTF2I alters behavior in an autistic sense, while the oral administration of a drug that inhibits GTF2I activity causes regress these symptoms. “Since, for the autistic spectrum, these are behavioral manifestations that can be caused by alterations in several hundred genes – comments Testa, corresponding author of the work – the challenge will be to understand whether this opportunity that is starting to open up for the 7Dup form can hopefully be also viable in a broader subgroup of autistic conditions”.
In Italy – recalls a UniMi note – developmental neuropsychiatric disorders affect almost 2 million children and young people, between 10% and 20% of the child and adolescent population between 0 and 17 years of age, with very different manifestations depending on type, course and prognosis, and the incidence is on the rise. Despite the high social, medical and economic impact, with the prevalence of autism spectrum disorders (ASD) now exceeding 1% and an even wider range if we consider all neurodevelopmental disorders as a whole, there are no pharmacological therapies for the main symptoms of the autism spectrum (social restriction, language deficits and stereotypies), above all due to the limited understanding of the molecular mechanisms, in turn linked to the lack of experimental models that recapitulate the alterations of human neurodevelopment in the most possible authentic and therefore physiopathologically relevant.
“This study – say Lopez-Tobon and Shyti – represents for neurodevelopmental disorders, and for autism in particular, the first example of a study which, going from the high-resolution molecular mechanism in human brain organoids up to the animal model, manages to establish, at a pre-clinical level, the potential feasibility of a pharmacological treatment of the main symptoms of autism”.
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