CORDIS - EU research results
CORDIS

Deacetylase inhibitors for autism spectrum disorders: an integrated preclinical validation pipeline in brain organoids and in vivo models

Project description

Deacetylase inhibitors as a novel approach in the treatment of autism spectrum disorders

Autism spectrum disorder (ASD) is a neurodevelopmental condition affecting more than 1% individuals with no effective treatment available. ASD is genetically heterogeneous, with hundreds of causative genetic lesions, despite the phenotypic similarities of its core symptoms, such as impaired language and restrictions in sociability. The duplication at 7q11.23 (7Dup) encompasses 26-28 genes and represents the best characterized ASD-causing copy number variations with translational potentials. A previous high-throughput screening on 7q11.23 copy number variations from patient-derived neurons revealed that deacetylase inhibition lowers the abnormal levels of a key gene underlying the cognitive/behavioral traits of 7Dup. The current EU-funded DUPDOWN project aims to generate proof of concept for the preclinical validation of selected deacetylase inhibitors in rescuing ASD phenotype in vitro and in vivo.

Objective

ASD is a very prevalent neurodevelopmental condition affecting more than 1% individuals, and represents a major unmet medical need since no effective treatment is available. Despite the phenotypic convergence of its core symptoms (impaired language, restriction in sociability and stereotypies, invariably coupled to anxiety and often associated to varying degrees of intellectual disability), ASD is genetically highly heterogeneous, with hundreds of bona fide causative genetic lesions. This genetic architecture breaks down ASD into a collection of rare and highly penetrant genetic syndromes, presenting key challenges but also decisive applicative opportunities: i) the accelerated regulatory path for drug approval/repurposing; and ii) the possibility that few paradigmatic syndromes may yield generalizable therapeutic inroads for ASD treatment. Duplication at 7q11.23 (7Dup), encompassing 26-28 genes, is one of best characterized ASD-causing copy number variations and offers unique translational opportunities, also because hemydeletion of the same interval causes Williams-Beuren syndrome, a condition characterized by hypersociability and language strengths, thereby providing a unique reference standard to validate treatments for the core ASD symptoms. Within my ERC-Consolidator project we successfully completed a high-throughput screening on 7q11.23 CNV patient-derived neurons and discovered that deacetylase inhibition lowers the abnormal levels of a key gene underlying the cognitive/behavioral traits of 7Dup. Having defined robust 7Dup neurodevelopmental and electrophysiological phenotypes, both in patients’ neuronal lineages and in mouse models, we now aim to generate proof of concept for the preclinical validation of selected deacetylase inhibitors in rescuing ASD phenotypes in vitro and in vivo. For this we pursue an integrated experimental and business plan, buttressed by key industrial partnerships, to advance the most inhibitors towards ASD treatment.

Host institution

UNIVERSITA DEGLI STUDI DI MILANO
Net EU contribution
€ 108 345,00
Address
Via Festa Del Perdono 7
20122 Milano
Italy

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Region
Nord-Ovest Lombardia Milano
Activity type
Higher or Secondary Education Establishments
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Total cost
No data

Beneficiaries (2)