Introduction

Autism Spectrum Disorder (ASD) refers to a large group of neurodevelopmental disorders that can be split, thanks to genetic diagnosis, into many rare genetic syndromes characterized by convergent core symptoms. There are no effective medications to cure ASD or ameliorate its core symptoms. Epi-OUTAUT research program focuses on rare autistic syndromes, including the 7DupASD caused by copy number variation of locus 7q11.23, and investigates classes of epigenetic modulators to treat ASD by tackling key mechanistic dysregulations that underlie its core symptoms.

Technical features

Prof. Giuseppe Testa’s research group has developed a unique collection of patients- specific neuronal models – disease avatars – including differentiated neurons and brain organoids, starting from pluripotent stem cells reprogrammed from skin fibroblasts of 7DupASD patients, representing uniquely relevant models exploitable for the identification of novel druggable targets. The interaction between the transcription factor GTF2I and the histone demethylase LSD1 (Lysine-specific demethylase 1) was identified as a new potential therapeutic target playing a critical role in the cognitive profile of 7DupASD patients. These findings allowed to identify IEO proprietary anti-LSD1 compounds as potential novel 7DupASD treatment. Proof-of-Concept studies showed that LSD1 inhibition reverts the ASD-relevant social deficits in 7DupASD mouse models. The effect of LSD1 inhibitors on 7DupASD core sociality symptoms and the availability of a platform of disease models for other rare neurodevelopmental disorders allows to expand the application of this treatment to other ASD syndromes sharing the same core symptoms and converging on the same molecular mechanism.

Possible Applications

• Treatment of core symptoms of 7DupASD;
• Treatment of core symptoms of other ASD syndromes sharing the same core symptoms and converging on the same molecular mechanism.

Advantages

• Proprietary first-in-class pharmacological agents ameliorating the ASD core symptoms;
• Reference reprogramming hub for the leading ASD mutations and largest human iPSC cohort of 7q11.23 CNV and related ASD syndromes;
• Invaluable patient-derived brain cortical organoid models recapitulating early human brain development in 3D and transgenic mouse models;
• Uniquely positioned network of clinical cohorts of 7DupASD worldwide.