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  • Periodic Report Summary 3 - DISEASEAVATARS (Modeling Disease through Cell Reprogramming: a Translational Approach to the Pathogenesis of Syndromes Caused by Symmetrical Gene Dosage Imbalances)
ERC

DISEASEAVATARS Report Summary

Project ID: 616441
Funded under: FP7-IDEAS-ERC
Country: Italy

Periodic Report Summary 3 - DISEASEAVATARS (Modeling Disease through Cell Reprogramming: a Translational Approach to the Pathogenesis of Syndromes Caused by Symmetrical Gene Dosage Imbalances)

WBS and 7dup-ASD are two neurodevelopmental disorders caused, respectively, by the loss or gain of 26-28 genes in chromosome 7. This symmetry of genetic lesion is reflected in largely symmetrical behavioural-cognitive profiles and facial dysmorphisms in patients: WBS are characterized by hypersociability with well-preserved language abilities, while 7dup-ASD, in contrast, have restricted sociality and severe language impairment. By measuring the amounts of transcribed RNA, translated RNA and proteins across all samples in our cohort of pluripotent cells derived from WBS, 7dup-ASD and healthy individuals, we managed to show how changes that originate at the first layer of gene expression (transcription) are retained, amplified or counteracted in other layers such as translation and protein abundance. This allows to understand in more detail how different dosages of genes in the WBS region can lead to alterations in development.
Furthermore, by implementing a recently published protocol, we were able to generate small tridimensional aggregates that are able to recapitulate in a physiologically meaningful way the spatio-temporal patterning and development of the human cerebral cortex, named “cortical spheroids”, which harbor the different types of neurons that originate during neuronal development. By externalizing cortical development in vivo, these organoids are granting us great insight into the cellular and molecular basis of WBS and 7dup-ASD, allowing us to visualize developmental processes and tissues that are hardly visible, let alone experimentally tractable, in developing humans.
Finally, we set up the conditions for a high-throughput screening (HTS) in patient-derived neurons, with the aim of identifying compounds capable of modulating the expression of the most relevant genes. The use of a highly reproducible protocol to generate cortical neurons, the attainment of pure neuronal cultures and their adaptation to an automated system to screen for active compounds constitute an innovative platform for the discovery of new leads in the area of intellectual disability and autism.

Reported by

UNIVERSITA DEGLI STUDI DI MILANO
Italy
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