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High-Throughput Drug Discovery for a Rare Neurological Disorder: Uncovering a Novel Therapeutic Opportunity for the 19q12 Autism Spectrum Disorder [19q12 neurons baseline data]

ABSTRACT: Discovering new and viable therapies for genetic diseases is a time consuming and cost intensive process. This is even more challenging for rare disorders that affect a small fraction of the population and do not incentivise research and development in the traditional drug discovery lifecycle. There is therefore a need for scalable and efficient solutions for discovering novel therapies for these rare disorders. In this study, we highlight how a high-throughput drug discovery engine was utilized to uncover drugs at scale that normalized the signature for a rare neurological neurodevelopmental disease, 19q12 autism spectrum disorder associated with deficiencies in ZNF536 and TSHZ3. We do this by uncovering and understanding the full 360o view of the biological impact of the drug in a relevant cell line via transcriptomics. This platform, in combination with a statistically viable n-of-1 trial, was able to quickly uncover and utilize a novel therapeutic potential of a previously approved drug for a patient living with from 19q12 autism spectrum disorder.

ORGANISM(S): Homo sapiens

PROVIDER: GSE292758 | GEO | 2025/03/24

REPOSITORIES: GEO

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High-Throughput Drug Discovery for a Rare Neurological Disorder: Uncovering a Novel Therapeutic Opportunity for the 19q12 Autism Spectrum Disorder [DRUGseq]

Project description:Discovering new and viable therapies for genetic diseases is a time consuming and cost intensive process. This is even more challenging for rare disorders that affect a small fraction of the population and do not incentivise research and development in the traditional drug discovery lifecycle. There is therefore a need for scalable and efficient solutions for discovering novel therapies for these rare disorders. In this study, we highlight how a high-throughput drug discovery engine was utilized to uncover drugs at scale that normalized the signature for a rare neurological neurodevelopmental disease, 19q12 autism spectrum disorder associated with deficiencies in ZNF536 and TSHZ3. We do this by uncovering and understanding the full 360o view of the biological impact of the drug in a relevant cell line via transcriptomics. This platform, in combination with a statistically viable n-of-1 trial, was able to quickly uncover and utilize a novel therapeutic potential of a previously approved drug for a patient living with from 19q12 autism spectrum disorder.

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Project description:We recently identified heterozygous deletions of the gene TSHZ3, which encodes a Zn-finger transcription factor, in patients with a syndrome including autistic features and provided evidence in mice for a link between Tshz3 haploinsufficiency, defects in cortical projection neurons (CPNs) and autism spectrum disorder (ASD)-like abnormalities. To get more insight into when and where TSHZ3 is required for the proper development of the brain, we generated and characterized a novel mouse model of conditional Tshz3 deletion in projection neurons from postnatal day 2-3 onward. These mice exhibit altered striatal expression of genes encoding for synaptic components, electrophysiological and synaptic changes in striatal cholinergic interneurons, , as well as ASD-relevant behavioral deficits. These data, by revealing a crucial postnatal role of TSHZ3 in the development and function of the corticostriatal circuitry that might be determinant for ASD pathogenesis, offer a novel ASD model and further open the possibility for an early postnatal therapeutic window for the syndrome linked to TSHZ3 haploinsufficiency.

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