Dottoressa di ricerca

ciclo: XXXVI

supervisore: Silvia Di Angelantonio
relatore: Silvia Di Angelantonio
co-supervisore: Silvia Di Angelantonio

Titolo della tesi: Targeting adenosine A2A receptor in FXS-patient derived human cortical culture for animal free drug discovery and repositioning.

Intellectual disabilities affect a significant percentage of the population, with Fragile X Syndrome (FXS) standing out as a prevalent neurodevelopmental disorder and a leading heritable cause of Autism Spectrum Disorders (ASDs). FXS is characterized by the loss of the fragile X mental retardation protein (FMRP), crucial for regulating mRNA associated with synaptic plasticity and neuronal development. Despite insights gained from animal models, translating findings into effective therapies for patients remains challenging due to species differences. The advent of human induced pluripotent stem cells (hiPSCs) provides a revolutionary platform, allowing for the modeling of FXS by incorporating patient-derived cells carrying the disease-causing mutation. This Ph.D. project aimed to investigate neurodevelopmental alterations in FXS at cellular and network levels, utilizing hiPSC-derived bidimensional cell cultures. These cultures, established from FXS patients and healthy controls, serve as reliable platforms for understanding the pathological mechanisms of FXS and facilitate drug discovery. The focus on a 2D culture model comprising neural progenitors, neurons, and glial cells revealed a persistent population of neural progenitor cells throughout neurodevelopment, highlighting FMRP's role in regulating progenitor proliferation and cortical specialization. Characterizing glutamatergic and GABAergic synapse development and assessing calcium activity within the neuronal network unveiled heightened activity and immaturity, consistent with FXS hallmarks. Leveraging this reliable cellular system, the study explored the therapeutic potential of istradefylline, an A2A receptor antagonist previously tested in FMRP-KO mice. Chronic treatment of FXS cell cultures demonstrated a significant rescue in cortical development and overall network activity. This study not only emphasizes the potential therapeutic value of istradefylline for FXS but also underscores the importance of humanized models in advancing treatments for neurodevelopmental disorders, including FXS.

Produzione scientifica

11573/1685183 - 2023 - Unlocking neural function with 3d in vitro models. A technical review of self-assembled, guided, and bioprinted brain organoids and their applications in the study of neurodevelopmental and neurodegenerative disorders
D’Antoni, Chiara; Mautone, Lorenza; Sanchini, Caterina; Tondo, Lucrezia; Grassmann, Greta; Cidonio, Gianluca; Bezzi, Paola; Cordella, Federica; Di Angelantonio, Silvia - 01a Articolo in rivista
rivista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (Basel (Matthaeustrasse 11) : Molecular Diversity Preservation International MDPI) pp. - - issn: 1661-6596 - wos: WOS:001030121200001 (7) - scopus: 2-s2.0-85165073149 (7)

11573/1661240 - 2022 - Human iPSC-Derived Cortical Neurons Display Homeostatic Plasticity
Cordella, Federica; Ferrucci, Laura; D'antoni, Chiara; Ghirga, Silvia; Brighi, Carlo; Soloperto, Alessandro; Gigante, Ylenia; Ragozzino, Davide Antonio; Bezzi, Paola; Di Angelantonio, Silvia - 01a Articolo in rivista
rivista: LIFE (Basel: MDPI) pp. 1884- - issn: 2075-1729 - wos: WOS:000895626200001 (4) - scopus: 2-s2.0-85149560233 (4)

11573/1645416 - 2022 - Culture of Human iPSC-Derived Motoneurons in Compartmentalized Microfluidic Devices and Quantitative Assays for Studying Axonal Phenotypes
Garone, M. G.; D'antoni, C.; Rosa, A. - 02a Capitolo o Articolo
libro: Stem Cell Assays: Methods and Protocols - (978-1-0716-1978-0; 978-1-0716-1979-7)

11573/1549009 - 2021 - Novel fragile X syndrome 2D and 3D brain models based on human isogenic FMRP-KO iPSCs
Brighi, Carlo; Salaris, Federico; Soloperto, Alessandro; Cordella, Federica; Ghirga, Silvia; De Turris, Valeria; Rosito, Maria; Porceddu, Pier Francesca; D'antoni, Chiara; Reggiani, Angelo; Rosa, Alessandro; Di Angelantonio, Silvia - 01a Articolo in rivista
rivista: CELL DEATH & DISEASE (Nature Group) pp. 1-22 - issn: 2041-4889 - wos: WOS:000656273400004 (31) - scopus: 2-s2.0-85105917597 (34)

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